Accepted Manuscript

Physical therapy vs. internet-based exercise training for patients with knee
osteoarthritis: Results of a randomized controlled trial

Kelli D. Allen, PhD, Liubov Arbeeva, MS, Leigh F. Callahan, PhD, Yvonne M.
Golightly, PT, MS, PhD, Adam P. Goode, PT, DPT, PhD, Bryan C. Heiderscheit, PT
PhD, Kim M. Huffman, MD PHD, Herbert H. Severson, PhD, Todd A. Schwartz, DrPH
PII: S1063-4584(17)31381-X
DOI: 10.1016/j.joca.2017.12.008
Reference: YJOCA 4137

To appear in: Osteoarthritis and Cartilage

Received Date: 31 May 2017

Revised Date: 4 December 2017
Accepted Date: 16 December 2017

Please cite this article as: Allen KD, Arbeeva L, Callahan LF, Golightly YM, Goode AP, Heiderscheit
BC, Huffman KM, Severson HH, Schwartz TA, Physical therapy vs. internet-based exercise training for
patients with knee osteoarthritis: Results of a randomized controlled trial, Osteoarthritis and Cartilage
(2018), doi: 10.1016/j.joca.2017.12.008.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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1 Title: Physical therapy vs. internet-based exercise training for patients with knee

2 osteoarthritis: Results of a randomized controlled trial

3 Authors:

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4 Kelli D Allen PhD 1, 2, 3 kdallen@email.unc.edu

5 Liubov Arbeeva, MS 1,2 liubov_arbeeva@med.unc.edu

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6 Leigh F Callahan PhD 1, 2 leigh_callahan@med.unc.edu

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7 Yvonne M Golightly PT, MS, PhD 1,,4,5 golight@email.unc.edu

8 Adam P Goode PT, DPT, PhD 6,7 adam.goode@duke.edu

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9 Bryan C Heiderscheit PT PhD 8 heiderscheit@ortho.wisc.edu

10 Kim M Huffman MD PHD 9.10 kim.huffman@duke.edu

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11 Herbert H. Severson, PhD 11 herb@ori.org

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12 Todd A Schwartz DrPH 1, 12, 13 Todd_Schwartz@unc.edu

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14 Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, 3300 Thurston
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15 Bldg., CB# 7280 Chapel Hill, NC 27599, USA

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16 Department of Medicine, University of North Carolina at Chapel Hill, 125 MacNider Hall CB#
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17 7005 Chapel Hill, NC 27599, USA

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18 Center for Health Services Research in Primary Care, Durham VA Medical Center, Durham,

19 NC, USA

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20 Injury Prevention Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC,

21 USA

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22 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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23 Duke Clinical Research Institute, Durham, NC, USA

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24 Department of Orthopedic Surgery, Division of Physical Therapy, Duke University Medical

25 Center

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26 Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, WI,

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27 USA

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28 Department of Medicine, Division of Rheumatology, Duke University Medical Center, Durham,

29 NC, USA

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30 Physical Medicine and Rehabilitation Service, Durham VA Medical Center, Durham, NC, USA
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31 Oregon Research Institute, Eugene, OR, USA

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32 Department of Biostatistics, Gillings School of Global Public Health, University of North
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33 Carolina at Chapel Hill, Chapel Hill, NC, USA

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34 School of Nursing, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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36 Abstract

37 Objective: To compare the effectiveness of physical therapy (PT, evidence-based approach)

38 and internet-based exercise training (IBET), each versus a wait list (WL) control, among

39 individuals with knee osteoarthritis (OA).

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40 Design: Randomized controlled trial of 350 participants with symptomatic knee OA, allocated

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41 to standard PT, IBET and WL control in a 2:2:1 ratio, respectively. The PT group received up to

42 8 individual visits within 4 months. The IBET program provided tailored exercises, video

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43 demonstrations, and guidance on progression. The primary outcome was the Western Ontario

44 and McMaster Universities Osteoarthritis Index (WOMAC, range 0 [no problems]-96 [extreme

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45 problems]), assessed at baseline, 4 months (primary time point) and 12 months. General linear
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46 mixed effects modeling compared changes in WOMAC among study groups, with superiority

47 hypotheses testing differences between each intervention group and WL and non-inferiority
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48 hypotheses comparing IBET with PT.

49 Results: At 4-months, improvements in WOMAC score did not differ significantly for either the
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50 IBET or PT group compared with WL (IBET: -2.70, 95% Confidence Interval (CI) = -6.24, 0.85,
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51 p=0.14; PT: -3.36, 95% (CI) = -6.84, 0.12, p=0.06). Similarly, at 12-months mean differences

52 compared to WL were not statistically significant for either group (IBET: -2.63, 95%CI = -6.37,
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53 1.11, p=0.17; PT: -1.59, 95% CI = -5.26, 2.08, p=0.39). IBET was non-inferior to PT at both time

54 points.
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55 Conclusions: Improvements in WOMAC score following IBET and PT did not differ

56 significantly from the WL group. Additional research is needed to examine strategies for

57 maximizing benefits of exercise-based interventions for patients with knee OA.

58 Key Words: Osteoarthritis, Knee, Physical Therapy, Internet, Physical Activity

59 Running Title: PT vs. Internet-Based Exercise for Knee OA

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60 Trial Registration: NCT02312713

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61 Introduction

62 Exercise is a recommended component of treatment for knee osteoarthritis (OA), based

63 on studies showing improvements in pain, function and other outcomes [1-3]. However, the

64 majority of adults with OA are inactive, highlighting the continued need for increasing regular

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65 engagement in exercise [4, 5]. Physical therapists can play a key role in instructing patients

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66 with OA in an appropriate exercise program (as well as deliver other treatments such as

67 orthotics, braces, gait aids and manual therapy), and physical therapy (PT) care is a

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68 recommended, evidence-based component of knee OA treatment [2, 6]. However, PT is

69 underutilized for knee OA [7-9], partly due to health care access-related issues, particularly for

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70 uninsured and under-insured patients and those in medically underserved areas. Individuals
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71 with lower socioeconomic status likely have the least access to a physical therapist or a

72 supervised exercise program, yet these individuals also bear a greater burden of OA [10, 11].
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73 Internet-based programs are an alternative, low-cost method for providing instruction

74 and support in appropriate exercise. However, there has been little research on internet-based
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75 exercise programs for patients with OA[12-15] or older adults[16, 17]. Further, there have been
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76 no direct comparisons of internet-based exercise programs with supervised exercise-based

77 therapies for knee OA. This study compared the effectiveness of an internet-based exercise
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78 training (IBET) program to in-person PT among individuals with symptomatic knee OA.

79 Specifically, this study tested whether PT or IBET were superior to a wait list (WL) control group
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80 at 4-month (primary time point) and 12-month follow-up. Additionally, analyses examined
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81 whether IBET was non-inferior to PT.

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83 Methods

84 This study was approved by the Institutional Review Boards of the University of North

85 Carolina at Chapel Hill (UNC) and Duke University Medical Center. Detailed methods have

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86 been published [18]. Recruitment occurred from November 2014-February 2016, and follow-up

87 assessments were completed in February 2017.

88 Study Design

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89 The PhysicAl THerapy vs INternet-Based Exercise Training for Patients with Knee Osteoarthritis

90 (PATH-IN) study was a pragmatic randomized controlled trial with participants assigned to

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91 standard PT, IBET and WL control, with allocation of 2:2:1, respectively. Randomization

92 schedules were computer generated by a statistician with stratification by recruitment source

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93 (UNC Healthcare system, Johnston County Osteoarthritis Project [19] and self-referral).

94 Participants continued with usual medical care for OA. Participants in the WL group did not

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receive PT or IBET during the study but were offered 2 PT visits and access to IBET following
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96 12-month assessments.

97 Participants and Recruitment

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98 Study inclusion criteria were: 1) Radiographic evidence of knee OA, physician diagnosis
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99 of knee OA in the medical record, or self-report of physician diagnosis along with items based
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100 on the American College of Rheumatology clinical criteria [20]. 2) Self-report of pain, aching or

101 stiffness in one or both knees on most days of the week. Exclusion criteria are shown in Box 1.
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102 Participants were recruited using two methods: 1) Active recruitment of patients with evidence

103 of knee OA in the UNC medical record, as well as participants with knee OA in the Johnston
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104 County Osteoarthritis Project [19]; these individuals were mailed an introductory letter, with
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105 telephone follow-up. 2) Advertisement within UNC and the surrounding communities. All

106 individuals who met eligibility criteria based on telephone-based screening completed consent

107 and baseline assessments in person. Participants were then given their randomization

108 assignment via telephone by the study coordinator.

109 Internet-Based Exercise Training Program

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110 The IBET program was developed by Visual Health Information and a multidisciplinary

111 team, including physical therapists, physicians and patients; details have been described [14].

112 Features of the IBET program include: 1) Tailored Exercises based on measures regarding

113 pain, function and current activity, along with an algorithm that assigns participants to one of

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114 seven different exercise levels. Exercise routines include strengthening, stretching and aerobic

115 activity recommendations. 2) Exercise Progression recommendations, based on serial

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116 measures of pain and function. 3) Video Display of Exercises (and photographs) to

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117 demonstrate proper exercise performance. 4) Automated Reminders to engage with the website

118 and remain active if participants have not logged in for seven days. 5) Progress Tracking,

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119 including graphs of pain, function, and exercise over time. Participants were asked to access

the IBET site as soon as they were randomized and to continue through the 12-month follow-up
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121 assessment. In accordance with current Department of Health and Human Services and other

guidelines for physical activity [21], participants were encouraged to complete strengthening and
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123 stretching exercises at least 3 times per week and to engage in aerobic exercises daily, or as
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124 often as possible.

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125 Physical Therapy

126 Physical therapists (with experience in treating OA) at multiple clinics administered the
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127 intervention following training by PT co-investigators (YMG, APG), who also performed periodic

128 fidelity checks. The PT intervention, described in detail elsewhere [18], was modeled after
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129 recommended elements of care provided to patients with knee OA [22], including: 1) evaluation
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130 of strength, flexibility, mobility, balance, function, knee alignment, and possible limb length

131 inequality; 2) evaluation of the need for assistive devices, knee braces, patellar taping, heel

132 lifts, shoe wedges and other footwear modifications; 3) instruction in an appropriate home

133 exercise program (including strengthening, stretching / range of motion, and aerobic exercises);

134 4) instruction in activity pacing and joint protection; 5) manual therapy, if appropriate; 6)

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135 modalities for pain management, if appropriate. Emphasis was placed on the home exercise

136 program, which was initiated at the first visit. To mirror standard clinical practice, physical

137 therapists were permitted to tailor visits to patients’ needs and functional limitations. Based on a

138 typical range of outpatient PT visits for knee OA, study participants could receive up to 8 one-

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139 hour sessions. At the first visit, physical therapists completed a standardized evaluation form

140 and documented treatment provided. At subsequent visits, physical therapists completed

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141 progress notes including documentation of treatment provided. The Appendix lists the guidance

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142 given to physical therapists.

143 Measures

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144 Baseline, 4-month and 12-month assessments were conducted by trained research

assistants blinded (via database restrictions) to participants’ randomization assignment.

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146 Assessments were typically conducted in person, though telephone-based follow-up

assessments were permitted in cases where participants are unable to return to the study site.
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148 Participants were paid $30 for completion of assessments at each time point.
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149
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150 Primary Outcome: Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC)

151 Total Score. The WOMAC is a measure of lower extremity pain (5 items), stiffness (2 items),
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152 and function (17 items) [23, 24]. All items were rated on a Likert scale of 0 (no symptoms) to 4

153 (extreme symptoms), with a total range of 0-96 and higher scores indicating worse symptoms.
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155 Secondary Outcomes: We examined the WOMAC pain (range 0 [no pain]-20 [extreme pain])

156 and function (range 0 [no difficulty] -68 [extreme difficulty]) subscales separately. We also

157 conducted four tests of physical function: the 30-second chair stand [25], the Timed Up and Go

158 Test (TUG) [26, 27], a two-minute step test [28], and unilateral stand time [29, 30]. The latter

159 was part of the Four-Stage Balance Test [30], and participants scored a “0” if they were unable

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160 to stand for 10 seconds in side-by-side, semi-tandem or tandem positions. Self-reported

161 physical activity was assessed with the Physical Activity Scale for the Elderly (PASE), which

162 measures occupational, household, and leisure activities during a 1-week period; the typical

163 range for the total PASE score is 0-400, with higher scores indicating greater activity [31]. In

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164 addition, participants self-reported their current minutes per week of stretching, strengthening

165 and aerobic exercise. Participants’ Global Assessment of Change in right and left knee

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166 (separately) pain, aching and stiffness was reported at follow-up assessments. This scale

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167 ranged from -6 (a very great deal worse) to +6 (a very great deal better); data were coded as

168 missing if participants never had symptoms in that knee or responded “don’t know.”

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169
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170 Intervention Delivery. We report the number of days on which participants in the IBET group

171 logged into the website and the number of PT visits attended. For each participant in the PT
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172 group we calculated the proportion of visits at which the therapist reported delivering specific

173 interventions.
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174

175 Non-Study PT Visits. At 4-month and 12-month follow-up, we asked participants whether they
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176 received PT care for knee OA outside the study since their last visit. This informed per-protocol

177 analyses described below.

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178
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179 Demographic and Clinical Characteristics. Self-reported participant characteristics included

180 age, race / ethnicity, gender, household financial state (with low income defined as self-report of

181 “just meeting basic expenses” or “don’t even have enough to meet basic expenses”), education

182 level (bachelor’s degree vs. less education), work status (employed vs. not working), marital

183 status, joints affected by OA, duration of OA symptoms, self-rated health (excellent, very good

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184 or good vs. fair or poor), and depressive symptoms (Patient Health Questionnaire-8) [32].

185 Height and weight were measured at baseline to calculate body mass index (BMI). Participants

186 also self-reported use of other OA treatments at both follow-up time points, including pain

187 medication use, knee injections, knee brace use, and topical creams.

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188 Adverse Event Assessment: Adverse events were identified through regular reports of

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189 participants’ visits to the UNC healthcare system, as well as through participants’ reports to

190 study team members.

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191 Sample Size

192 As detailed elsewhere [1], the sample size estimate of n=350 was based on the

193
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hypothesis of non-inferiority, which is the most conservative [33-35], and on the 2:2:1
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194 randomization ratio [36]. A one-sided, two-sample t-test sample size calculation was used at the

195 0.025 significance level for the difference in mean WOMAC between IBET and PT to be less
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196 than 5 points at 4-month follow-up, with an adjustment to the variance to account for repeated

197 measures [37] and potential 10% attrition.

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198 Data Analyses

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199 We tested four hypotheses: H1: Participants who receive either IBET or standard PT will

200 have clinically relevant improvements in WOMAC at 4-month follow-up, compared with WL
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201 control group. H2: IBET (a new intervention) will be non-inferior to PT (an intervention with

202 established evidence [6]) at 4-month follow-up, indicated by a mean WOMAC score less than
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203 five points higher (worse) than PT. For total WOMAC scores, a 5 point non-inferiority margin
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204 was selected because it is on the border of what would be considered a clinically important

205 effect in this context [38, 39]. H3 and H4 mirrored H1 and H2 but at the 12-month follow-up time

206 point. For the superiority hypotheses (H1, H3), primary conclusions were based on intention-to-

207 treat (ITT) analyses, with participants assigned to the arm to which they were randomized,

208 regardless of adherence, using all available follow-up data [40]. For non-inferiority hypotheses

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209 (H2, H4), the ITT analysis would not necessarily be the conservative approach [41]. We

210 therefore performed analyses on both an ITT and per-protocol basis [35, 42]. For the latter we

211 excluded individuals who did not adhere to their assigned study group, including those in the PT

212 group (N=9) who attended no visits, those in the IBET group who did not log on to the website

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213 (N=28), and those in the IBET (N=5) and WL (N=4) groups who received PT outside the study.

214 A general linear mixed effects model was fitted with changes from baseline in WOMAC

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215 scores as the dependent variables with an unstructured covariance matrix to account for the two

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216 follow-up repeated measures. Fixed effects included follow-up time, intervention group, their

217 interaction, baseline WOMAC score, and enrollment source. The SAS MIXED procedure (Cary,

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218 NC) was used to fit these models and to test linear contrasts corresponding to each hypothesis.

Participants missing either follow-up measurement were still included in the model under a
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220 ‘missing at random’ paradigm. Sensitivity analyses were also conducted through multiple

imputation of missing values (see below).

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222 To test the null hypothesis of non-inferiority of IBET versus standard PT at 4 months in
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223 management of OA symptoms, the 95% confidence interval (CI) of the appropriate linear
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224 contrast was constructed; non-inferiority was concluded if the upper limit of the interval was less

225 than the non-inferiority margin of 5 points [42]. Superiority hypotheses involved two
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226 comparisons versus WL control, so each was conducted at the two-sided .025 significance

227 level. The non-inferiority hypotheses involve only one comparison and were tested at the full
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228 one-sided .025 significance level.

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229 We had several strategies for handling missing data. When individual items were

230 missing from self-report scales, we followed guidelines regarding when to impute scores [43].

231 When guidelines were unavailable, we treated the scale as missing if >1 item was missing;

232 when 1 item was missing we substituted with the mean of available items. When participants

233 declined or could not complete function tests they were assigned the lowest value for that test;

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234 when participants ran out of time to complete function tests or assessments were completed via

235 telephone, data were treated as missing. In some cases (4 at 4-months, 5 at 12-months), our

236 data coding scheme did not allow us to differentiate between these two situations; these were

237 treated as missing. For sensitivity analysis for the ITT approach, we performed multiple

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238 imputation to deal with missing data at follow-up assessments via the SAS MI and MIANALYZE

239 procedures, specifying 30 imputations. First, three missing race values were imputed based on

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240 other participant characteristics. Then we identified baseline characteristics that differed

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241 between completers and non-completers at follow-up at the p≤0.25 level. These characteristics

242 were used to impute missing baseline WOMAC values. Next, missing 4-month WOMAC scores

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243 were imputed as a function of these baseline characteristics, baseline WOMAC score, and

treatment group; imputation of 12-month WOMAC score also included 4-month WOMAC
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245 scores. The same imputation process was followed for secondary outcomes.

Corresponding analytic strategies were used for secondary outcomes, though there was
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247 insufficient information in the literature to define a non-inferiority margin for these measures.
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248 Additionally, as the Global Assessment of Change variables do not have baseline values, the
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249 actual values (rather than change from baseline) were managed as the response variable, with

250 no baseline score as a covariate. A square root transformation was used for the weekly
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251 minutes of exercise variables to improve the residuals with respect to the normality assumption.

252 To provide comparison with prior studies, we calculated standardized mean differences (SMDs)
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253 for WOMAC total and subscale scores for both intervention groups compared to WL (ratio of
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254 model-predicted mean group differences to their pooled standard deviation (SD).

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256 Results

257 Participants and Retention

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258 We identified 11,274 potential participants from all recruitment sources (Figure 1). Of

259 683 who completed telephone screening, 350 (51%) were eligible, enrolled and randomized.

260 Because randomization was stratified by enrollment source, allocation across groups was

261 slightly different than the 2:2:1 ratio, with 142 participants assigned to the IBET group, 140 to

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262 the PT group and 68 to the WL group. At both 4-month and 12-month follow-up, 86% of

263 participants completed primary outcomes (Figure 1). Compared with participants who

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264 completed follow-up assessments for the primary outcome at 12-months, non-completers had a

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265 higher baseline mean WOMAC total score (31.2, SD = 17.6 vs. 37.6, SD = 19.1, respectively).

266 Participant characteristics are shown in Table 1. Participants’ use of other OA treatments at

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267 follow-up was similar across groups (Appendix Table 1).
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269 Adverse Events
270 There were 4 non-serious study-related events in the PT group (1 fall, 3 increased knee pain)
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271 and 4 in the IBET group (2 increased knee pain, 1 shoulder pain, 1 ankle pain).
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273 Intervention Delivery

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274 Between baseline and 4-month follow-up, 114 (80%) of participants in the IBET group

275 logged onto the website; the mean (SD) number of days logged on was 20.7 (24.6),
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276 median=9.5. Between baseline and 12-month follow-up, 115 (81%) of participants in the IBET

277 group logged onto the website with a mean (SD) number of days logged on of 40.5 (59.8)
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278 median=10.5. The mean number of days logged onto the website between 4-month and 12-
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279 month follow-up was 19.8 (37.7), median=0. Seven physical therapists contributed to

280 intervention delivery, with numbers of participants treated by each PT ranging from 2-40; this

281 wide range was primarily due to participants’ geographic proximity to the different study PT

282 clinics. Among participants in the PT group, 131 (94%) attended at least one visit; 51% attended

283 6-8 visits. The mean (SD) number of visits was 5.7 (2.5), with a median of 7.0 visits. The mean

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284 proportions of visits per patient at which therapists reported delivering specific intervention

285 components were: Therapeutic Exercise – 94%; Balance / Neuromuscular Education – 38%;

286 Manual Therapy – 43%; Gait / Strength Training – 44%; Modalities – 29%; and Shoes / Wedges

287 – 20%.

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289 Primary Outcome: WOMAC Total Score

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290 Intention-To-Treat Analyses

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291 Superiority Hypotheses: Neither IBET nor PT were superior to WL at 4 months or 12

292 months at the specified p<0.025 (Table 2, Figure 2). Multiple imputation analyses showed

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293 similar results for both interventions (Appendix Table 2). At 4-months, the SMDs for PT and

IBET group, respectively were -0.26 (-0.53, 0.00) and -0.20 (-0.48, 0.07), compared to the WL
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295 group (Table 3). At 12-months, the SMDs for PT and IBET group, respectively were -0.12 (-

0.40, 0.16) and -0.19 (-0.46, 0.09), compared to the WL group.

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297 Non-Inferiority Hypotheses: Compared to PT, IBET effects were within the pre-specified
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298 non-inferiority limit of 5 points on the WOMAC total score at both 4-months (estimate = 0.67,
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299 95% CI=-2.23, 3.56; p=0.65) and 12-months (estimate = -1.04, 95% CI=-5.26, 2.08; p=0.39),

300 Figure 3.
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301 Per-Protocol Analyses: Per-protocol analyses yielded similar results (Appendix Table 3):

302 The greatest difference was between PT and WL at 4 months (-3.65, 95% CI = -7.34, -0.03,
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303 p=0.05). Differences between IBET and PT were within the pre-specified non-inferiority limit at
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304 both time points.

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306 Secondary Outcomes

307 WOMAC subscales: In ITT analyses, changes in WOMAC pain and function did not

308 differ significantly between either intervention group and WL at 4 or 12 months (Table 2).

309 There were also no statistically significant differences between PT and IBET (Appendix Table

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310 4). Results were similar in multiple imputation and per-protocol analyses for both WOMAC

311 subscales (Appendix Tables 2 and 3). Table 3 shows SMDs for both interventions compared to

312 WL.

313 PASE and Weekly Minutes of Exercise: At 4 months there were no significant

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314 differences in PASE subscale scores across groups (Table 2). At 12 months the PT group had

315 significantly greater improvement in PASE Leisure subscale score compared to WL (p=0.02).

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316 There were no notable differences in multiple imputation or per-protocol analyses of PASE

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317 scores (Appendix Tables 2 and 3). There were no significant differences in weekly minutes of

318 strengthening or aerobic exercise across groups at either time point (Table 2). The PT group

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319 reported greater weekly minutes of stretching than WL at both 4 and 12 months, and the IBET

reported greater minutes than WL at 12 months. Results were similar in multiple imputation
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321 analyses. In per protocol analyses, the PT group reported greater minutes of strengthening at 4

months and aerobic activity at 12 months compared to WL; the IBET group reported greater
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323 minutes of aerobic activity at 4 and 12 months.

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324 Functional tests: For both unilateral stand time and the 30 second chair stand test, there
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325 were minimal within-group changes over time and no between-group differences when using

326 ITT (Table 2), multiple imputation or per-protocol analyses (Appendix Tables 2 and 3). For the
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327 2-minute march test, the largest difference was between the PT and WL groups at 4 months

328 (ITT estimate = 7.75, 95% CI = 0.43, 15.07, p=0.04), favoring the PT group; using multiple
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329 imputation, this difference was 8.97 (95% CI = 1.68, 16.26, p=0.02). There were no statistically
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330 significant differences in the TUG test for the PT or IBET groups compared to the WL group

331 (Appendix Table 2).

332 Global Assessment of Knee Symptom Change: In ITT analyses for the right knee, the

333 PT group reported greater improvement than WL at 4 and 12 months, and the IBET group

334 reported greater improvement than WL at 12 months (Table 2). At 4 months, IBET reported less

335 improvement than the PT group. For the left knee, the PT group reported more improvement

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336 than WL at 4 months, and the IBET group reported more improvement than WL at 12 months.

337 Results were similar for multiple imputed and per protocol analyses.

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339 Discussion

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340 In this study there were no statistically significant nor clinically meaningful differences in

341 most study outcomes, including total WOMAC score, between intervention groups and the WL

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342 group. IBET was non-inferior to PT at both 4 and 12 months for the primary outcome.

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343 Given prior studies on the effectiveness of exercise and PT care for knee OA [3, 6, 44], it

344 is unclear why the PT intervention was not superior to WL for most outcomes. It is challenging

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345 to compare effects across PT-based interventions due to heterogeneity in dose (e.g. number

and duration of sessions), type and duration. However, a meta-analysis of PT-related

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347 interventions for knee OA found that with respect to pain, SMDs were -0.21 (-0.35, -0.08) and -

0.69 (-1.24, -0.14) for programs focusing on aerobic and strengthening exercise, respectively
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349 [6]. The SMD for pain immediately following our PT intervention was smaller than these (-0.14)
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350 and declined at 12 months. The meta-analysis found that with respect to disability / function,
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351 SMDs were -0.21 (-0.37, -0.04) and -0.16 (-0.48, -0.16), for programs focusing on aerobic and

352 strengthening exercise, respectively. The SMD for function immediately after our PT
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353 intervention was somewhat larger than these -(0.27), but declined to 0.19 at 12 months.

354 Therefore, our PT intervention was comparable to pooled estimates of prior PT-related studies
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355 regarding function but less effective with respect to pain; overall these effect sizes were small.
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356 We aimed for the PT intervention to mirror standard practice, but effects may have been more

357 robust with a greater exercise dose. Recent meta-analyses of OA studies indicate that exercise-

358 based interventions adhering to American College of Sports Medicine dose recommendations

359 resulted in larger improvements [44, 45]. Additional work is needed to develop strategies for

360 standardizing and implementing these recommendations within the structure and limited number

361 of visits typically allowed for routine PT care for knee OA.

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362 Although IBET was non-inferior to PT for most outcomes, these results should be

363 interpreted in light of the small, non-significant effects of the PT intervention. Effect sizes for the

364 IBET intervention were also small. There has been little research on internet-based exercise

365 programs for knee OA, but in two prior studies, effects were somewhat greater than in our study

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366 [14, 15]. Both of those prior studies recruited participants via self-referral or opt-in after clinician

367 referral, which may have resulted in more highly motivated samples with greater “readiness to

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368 change” compared to our participants, who recruited participants proactively by the study team

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369 [18]. Engagement with the IBET program was relatively low, highlighting the need for

370 strategies to facilitate use of these types of programs and identify patients who may be most

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371 likely to benefit.

There are several limitations to our study. First, we did not confirm OA diagnosis with
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372

373 standardized de novo radiographs or independent physician assessments. However, all

participants had either a prior radiographic or physician diagnosis of OA (in the medical record
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374

375 or self-reported), so it is very unlikely there were participants without either radiographic or
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376 symptomatic OA. Second, self-reported physical activity is often over-reported. However, it is
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377 unlikely that this differed among study groups. Third, we did not assess adherence to home

378 exercise. Fourth, because this was a pragmatic study, physical therapists were permitted to vary
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379 the intervention in terms of specific exercises assigned and intensity, based on participant

380 needs; this approach has advantages regarding the study of real-world PT practice but presents
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381 challenges in evaluating effects of a specific exercise dose. Fifth, this study was conducted in
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382 one geographic region and only included participants with regular internet access, which may

383 limit generalizability of findings. Sixth, this sample was relatively well educated, and results may

384 not generalize to patient groups with lower education levels.

385 In conclusion, in this pragmatic study neither the PT nor IBET intervention resulted in

386 statistically significant or clinically relevant improvement in most outcomes, compared to a WL

387 control group. Effects of both interventions may have been robust if the dose had been greater

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388 [44, 45]. In agreement with a recent systematic review [46], results of this study suggest

389 additional research is needed to develop strategies for maximizing the effectiveness of PT

390 interventions, including understanding which PT treatments work best for which patients and

391 optimizing intervention dose in the context of real-world clinical settings.

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392

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393 Acknowledgements

394 The study team thanks all of the study participants, without whom this work would not be

395 possible. We also thank the following team members for their contributions to the research:

396 Caroline Nagle, Kimberlea Grimm, Ashley Gwyn, Bernadette Benas, Alex Gunn, Leah

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397 Schrubbe, and Quinn Williams. The study team also expresses gratitude to the Stakeholder

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398 Panel for this project: Ms. Sandy Walker LPN (Chapel Hill Children's Clinic), Ms. Susan

399 Pedersen RN BSN, Ms. Sally Langdon Thomas, Mr. Ralph B. Brown, Ms. Frances Talton CDA

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400 RHS Retired, Dr. Katrina Donahue, MD, MPH (Department of Family Medicine at the University

401 of North Carolina at Chapel Hill), Dr. Alison Brooks, MD, MPH (Department of Orthopedics &

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402 Rehabilitation at the University of Wisconsin-Madison), Dr. Anita Bemis-Dougherty, PT, DPT,
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403 MAS (American Physical Therapy Association), Dr. Teresa J. Brady, PhD (Centers for Disease

404 Control and Prevention), Ms. Laura Marrow (Arthritis Foundation National Office), Ms. Megan
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405 Simmons Skidmore (American Institute of Healthcare and Fitness), and Dr. Maura Daly Iversen,

406 PT, DPT, SD, MPH, FNAP, FAPTA (Department of Physical Therapy, Movement and
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407 Rehabilitation Sciences Northeastern University). The study team thanks study physical
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408 therapists and physical therapy assistants: Jennifer Cooke, PT, DPT, Jyotsna Gupta, PT, PhD

409 and Carla Hill, PT, DPT, OCS, Cert MDT (Division of Physical Therapy, University of North
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410 Carolina at Chapel Hill), Bruce Buley, Andrew Genova, and Ami Pathak (Comprehensive

411 Physical Therapy, Chapel Hill, NC), Chris Gridley and Aaron Kline (Pivot Physical Therapy,
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412 Smithfield, NC).

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413 Authors Contributions

414 KDA, LA, LFC, YMG, APG, BCH, KMH, HS and TAS contributed to the study design and

415 protocol and helped draft the manuscript. HS and BCH contributed to the original design and

416 evaluation of the exercise website. TS and LA contributed to plans for and conduct of statistical

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417 analyses. All authors read and approved the final manuscript. YMG and APG oversaw design

418 and fidelity checks for the physical therapy intervention.

419

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420 Role of the Funding Source

421 This study was funded through a Patient-Centered Outcomes Research Institute Award (CER-

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422 1306-02043). The statements, opinions] presented in this manuscript are solely the

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423 responsibility of the authors and do not necessarily represent the views of the Patient-Centered

424 Outcomes Research Institute, its Board of Governors or Methodology Committee. KDA, LA,

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425 LFC, YMG, APG, and TAS receive support from National Institute of Arthritis and

426 Musculoskeletal and Skin Diseases Multidisciplinary Clinical Research Center P60 AR062760
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427 KDA receives support from the Center for Health Services Research in Primary Care, Durham

428 VA Health Care System (CIN 13-410).

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429 Competing Interests

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430 Visual Health Information, Inc (VHI) owns the website used in the current manuscript.
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431 Heiderscheit and Seversen have received consulting fees from VHI. A patent related to the

432 website described in this manuscript is currently under review.

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433
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Appendix: Guidance for Structure and Content of Physical Therapy Visits

1. Programs, both in the clinic and at home, should be comprehensive and functional,
focusing on core and lower body function, but can be tailored to meet the functional
abilities, needs and deficits of each participant.
2. Each visit should emphasize therapeutic exercise and include muscle strengthening,

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stretching/flexibility/range of motion, and aerobic exercise.
3. Education on activity pacing, joint protection and pain management

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4. A home program should be recommended during the 1st visit and should be progressed
over the course of treatment.
5. Home programs should emphasize the following:

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a. Strengthening Exercises
i. Recommend performing strengthening exercises 2-3 times per week

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ii. Include functional exercises, such as gait or stair training and
neuromuscular education
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b. Stretching/flexibility/range of motion Exercises
i. Recommend performing range of motion exercises daily
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c. Aerobic Exercises
i. Promote “lifestyle” physical activity
ii. Encourage moderate intensity exercise
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iii. Episodes of activity should last at least 10 minutes, if the participant is

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able
iv. Episodes should be spread out throughout the week with a long-term goal
of working up to a total of 150 minutes of activity per week
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v. Aerobic exercise can be weight-bearing, reduced weight-bearing or non-

weight-bearing.
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6. Modalities for pain management can be included during the clinic visit and as part of the
home program. Modalities should be used conservatively, taking no more than 25% of
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the time of each clinic visit.

7. If appropriate, manual therapy and / or patellar taping can be provided during the clinic
visit.
8. Shoes should be assessed during the first visit, and shoe recommendations should be
provided, if appropriate.
9. If limb length inequality or frontal plane knee malalignment is suspected, treatment with
shoe lifts or shoe wedges, respectively, should be attempted.
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Appendix Table 1: Proportions of Participants Reporting Use of Specific Osteoarthritis

Treatments by Group and Follow-Up Time Point
% of Participants Self-Reporting Use of Internet-Based Physical Therapy Wait List
Treatment Exercise Training
Pain Medications for Osteoarthritis
4-Month Follow-Up 65% 55% 60%
12-Month Follow-Up 59% 57% 52%

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Knee Injection Since Baseline
4-Month Follow-Up 7% 7% 12%
12-Month Follow-Up 14% 12% 21%
Physical Therapy (Non-Study) for Knee

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Osteoarthritis Since Last Study Visit
4-Month Follow-Up 5% 1% 7%
12-Month Follow-Up 12% 7% 11%

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Knee Brace (Current)
4-Month Follow-Up 19% 19% 20%
12-Month Follow-Up 19% 20% 17%
Topical Creams (Current)

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4-Month Follow-Up 24% 23% 22%
12-Month Follow-Up 29% 28% 24%
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Appendix Table 2. Within- and Between-Group Mean Changes in Outcomes and 95% Confidence Intervals:
Results of Intention-to-Treat Analyses with Multiple Imputation
Difference in Baseline to Baseline to 12- Difference in Baseline to
Baseline to 4-Month 4-Month vs. WL (95% CI), Month Difference 12-Month vs. WL (95%
Outcome Difference (95% CI) p-value (95% CI) CI), p-value
WOMAC Total
WL -3.29 (-6.29,-0.29) -- -2.95 (-6.04,0.15) --
PT -6.85 (-9.01,-4.69) -3.56 (-7.16,0.04), 0.05 -4.72 (-6.96,-2.48) -1.77 (-5.38,1.84), 0.34
IBET -6.00 (-8.19,-3.82) -2.71 (-6.28,0.86), 0.14 -5.68 (-8.03,-3.32) -2.73 (-6.50,1.04), 0.16

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WOMAC
Function
WL -2.31 (-4.45,-0.17) -- -1.63 (-3.95,0.68) --
PT -4.97 (-6.50,-3.43) -2.66 (-5.20,-0.11), 0.04 -3.39 (-5.04,-1.75) -1.76 (-4.48,0.96), 0.21

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IBET -3.97 (-5.57,-2.37) -1.66 (-4.29,0.97), 0.22 -3.75 (-5.41,-2.10) -2.12 (-4.85,0.62), 0.13
WOMAC Pain
WL -0.65 (-1.4,0.10) -- -0.65 (-1.39,0.09) --
PT -1.12 (-1.66,-0.58) -0.47 (-1.36,0.41), 0.29 -0.71 (-1.26,-0.17) -0.06 (-0.94,0.81), 0.89

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IBET -1.53 (-2.12,-0.95) -0.89 (-1.8,0.03), 0.06 -1.12 (-1.65,-0.58) -0.47 (-1.33,0.40), 0.29
PASE Total
WL -2.72 (-19.05,13.61) -- 1.96 (-12.93,16.85) --
PT 2.49 (-9.08,14.07) 5.21 (-13.91,24.33), 0.59 7.91 (-2.86,18.69) 5.95 (-11.31,23.22), 0.50

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IBET -11.25 (-24.37,1.88) 8.53 (-27.33,10.26), 0.37 9.43 (-2.12,20.99) 7.47 (-10.23,25.18), 0.41
PASE Leisure
WL -2.73 (-8.15,2.69) -- -0.23 (-6.49,6.03) --
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PT 4.01 (0.44,7.58) 6.74 (0.56,12.92), 0.03 8.81 (4.45,13.16) 9.04 (1.67,16.40), 0.02
IBET -1.00 (-4.91,2.91) 1.74 (-4.59,8.06), 0.59 7.69 (3.09,12.28) 7.92 (0.55,15.29), 0.04
PASE Household
WL
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PT -5.65 (-14.68,3.37) -- -4.05 (-12.07,3.97) --

IBET -2.05 (-8.34,4.24) 3.60 (-7.05,14.25), 0.51 2.02 (-3.85,7.88) 6.07 (-3.55,15.68), 0.22
-8.83 (-15.61,-2.05) -3.18 (-14.04,7.69), 0.57 -4.12 (-10.69,2.44) -0.07 (-10.06,9.92), 0.99
PASE Work
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WL 4.38 (-6.81,15.56) -- 5.67 (-4.10,15.44) --

PT 1.45 (-6.01,8.91) -2.93 (-15.79,9.93), 0.66 -2.76 (-9.64,4.11) -8.43 (-19.85,2.98), 0.15
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IBET -1.32 (-9.51,6.87) -5.70 (-19.48,8.08), 0.42 5.87 (-1.30,13.04) 0.20 (-11.46,11.86), 0.97
Unilateral Stand
Time
WL -0.12 (-0.90,0.66) -- -0.14 (-0.94,0.65) --
PT -0.53 (-1.08,0.02) -0.41 (-1.32,0.50), 0.38 -0.02 (-0.55,0.52) 0.13 (-0.81,1.06), 0.79
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IBET 0.08 (-0.53,0.70) 0.20 (-0.77,1.18), 0.68 0.02 (-0.54,0.58) 0.16 (-0.78,1.11), 0.73
30 Second Chair
Stand
WL 0.10 (-0.95,1.16) -- 0.55 (-0.38,1.49) --
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PT -0.06 (-0.80,0.68) -0.16 (-1.41,1.09), 0.80 0.13 (-0.54,0.80) -0.43 (-1.54,0.69), 0.45
IBET 0.67 (-0.10,1.43) 0.56 (-0.72,1.85), 0.39 0.86 (0.18,1.55) 0.31 (-0.84,1.45), 0.60
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2 Minute March
Test
WL -8.83 (-14.99,-2.67) -- -0.09 (-6.67,6.50) --
PT 0.14 (-4.20,4.48) 8.97 (1.68,16.26), 0.02 1.06 (-3.68,5.79) 1.14 (-6.69,8.98), 0.77
IBET -2.38 (-6.88,2.11) 6.45 (-0.99,13.88), 0.09 1.35 (-3.51,6.20) 1.43 (-6.80,9.67), 0.73
Timed Up and Go
WL -0.11 (-1.14,0.91) -- -0.31 (-1.43,0.80) --
PT -0.56 (-1.30,0.17) -0.45 (-1.63,0.73), 0.45 -0.94 (-1.75,-0.13) -0.62 (-1.98,0.73), 0.37
IBET -0.90 (-1.74,-0.06) -0.79 (-2.08,0.50), 0.23 -1.47 (-2.36,-0.58) -1.16 (-2.58,0.27), 0.11
Weekly Minutes
of Aerobic
Activity *
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WL -0.05 (-1.48,1.38) -- -1.68 (-3.32,-0.05) --

PT 0.98 (-0.03,1.99) 1.03 (-0.67,2.73), 0.23 0.51 (-0.65,1.66) 2.19 (0.24,4.13), 0.03
IBET 1.88 (0.76,3) 1.93 (0.25,3.62), 0.02 0.49 (-0.77,1.74) 2.17 (0.15,4.18), 0.03
Weekly Minutes
of Stretching*
WL -0.36 (-1.38,0.65) -- -1.29 (-2.19,-0.38) --
PT 1.45 (0.76,2.15) 1.81 (0.62,3), 0.00 0.36 (-0.28,1) 1.65 (0.58,2.72), 0.00
IBET 1.08 (0.31,1.85) 1.44 (0.22,2.67), 0.02 0.8 (0.09,1.51) 2.09 (1,3.17), 0.00

PT
Weekly Minutes
of
Strengthening*
WL 0.43 (-0.69,1.55) -- -0.1 (-1.28,1.08) --

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PT 1.85 (1.04,2.65) 1.42 (0.11,2.72), 0.03 1.17 (0.33,2.02) 1.27 (-0.12,2.67), 0.07
IBET 1.47 (0.63,2.32) 1.04 (-0.31,2.39), 0.13 1.32 (0.38,2.26) 1.42 (-0.03,2.87), 0.05
Patient Global
Assessment of

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Change – Right
Knee
WL 0.14 (-0.39,0.67) -- -0.17 (-0.69,0.36) --
PT 1.36 (0.97,1.74) 1.22 (0.58,1.86), 0.00 0.60 (0.2,1.01) 0.77 (0.14,1.4), 0.02

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IBET 0.43 (0.04,0.83) 0.30 (-0.33,0.92), 0.35 0.53 (0.13,0.94) 0.70 (0.04,1.36), 0.04
Patient Global
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Assessment of
Change – Left
Knee
WL -0.1 (-0.66,0.45) -- -0.39 (-0.96,0.17) --
PT 0.94 (0.56,1.33) 1.05 (0.4,1.7), 0.00 0.16 (-0.27,0.59) 0.55 (-0.14,1.24), 0.11
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IBET 0.50 (0.1,0.9) 0.60 (-0.07,1.27), 0.08 0.58 (0.15,1.02) 0.98 (0.28,1.68), 0.00
* A square root transformation was applied due to superior diagnostics in statistical models.
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Appendix Table 3. Within- and Between-Group Mean Changes in Outcomes and 95% Confidence Intervals:
Results of Per Protocol Analyses
Difference in Baseline to Baseline to 12- Difference in Baseline to
Baseline to 4-Month 4-Month vs. WL (95% CI), Month Difference 12-Month vs. WL (95%
Outcome Difference (95% CI) p-value (95% CI) CI), p-value
WOMAC Total
WL -3.64 (-6.8,-0.48) -- -2.74 (-6,0.53) --
PT -7.29 (-9.56,-5.03) -3.65 (-7.34,0.03), 0.05 -4.71 (-7.07,-2.35) -1.97 (-5.81,1.86), 0.31
IBET -6 (-8.53,-3.46) -2.36 (-6.23,1.51), 0.23 -5.84 (-8.48,-3.19) -3.1 (-7.13,0.93), 0.13
WOMAC

PT
Function
WL -2.48 (-4.79,-0.18) -- -1.37 (-3.72,0.97) --
PT -5.2 (-6.83,-3.56) -2.71 (-5.4,-0.02), 0.05 -3.58 (-5.26,-1.9) -2.21 (-4.96,0.55), 0.11
IBET -3.79 (-5.63,-1.95) -1.31 (-4.13,1.52), 0.36 -3.75 (-5.65,-1.86) -2.38 (-5.27,0.51), 0.11

RI
WOMAC Pain
WL -0.7 (-1.49,0.09) -- -0.68 (-1.46,0.1) --
PT -1.19 (-1.75,-0.62) -0.49 (-1.41,0.43), 0.29 -0.69 (-1.25,-0.13) -0.01 (-0.92,0.9), 0.98
IBET -1.59 (-2.22,-0.95) -0.89 (-1.86,0.08), 0.07 -1.16 (-1.79,-0.53) -0.49 (-1.44,0.47), 0.32

SC
PASE Total
WL -2.95 (-20.41,14.51) -- 2.36 (-12.43,17.15) --
PT 2.39 (-9.73,14.51) 5.34 (-15.13,25.81), 0.61 8.33 (-2.3,18.96) 5.97 (-11.29,23.23), 0.50
IBET -8.85 (-22.92,5.22) -5.9 (-27.55,15.75), 0.59 7.94 (-4.41,20.29) 5.58 (-12.77,23.93), 0.55

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PASE Leisure
WL -2.7 (-8.17,2.77) -- -0.79 (-7.26,5.68) --
PT 3.39 (-0.42,7.19) 6.08 (-0.26,12.42), 0.06 7.93 (3.34,12.52) 8.72 (1.07,16.37), 0.02
AN
IBET -1.19 (-5.56,3.18) 1.51 (-5.18,8.2), 0.66 7.54 (2.24,12.84) 8.33 (0.24,16.42), 0.04
PASE
Household
WL -3.48 (-13.05,6.1) -- -1.79 (-10.37,6.78) --
M

PT -0.57 (-7.24,6.1) 2.9 (-8.35,14.16), 0.61 3.4 (-2.78,9.58) 5.19 (-4.9,15.28), 0.31
IBET -8.55 (-16.33,-0.76) -5.07 (-17.02,6.88), 0.40 -3.1 (-10.25,4.05) -1.3 (-12.02,9.41), 0.81
PASE Work
WL 2.27 (-9.4,13.93) -- 5.25 (-4.77,15.26) --
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PT 0.42 (-7.61,8.46) -1.84 (-15.53,11.84), 0.79 -2.93 (-10.07,4.21) -8.18 (-19.91,3.55), 0.17
IBET -0.95 (-10.18,8.28) -3.22 (-17.64,11.2), 0.66 4.18 (-3.94,12.3) -1.07 (-13.41,11.28), 0.86
TE

Unilateral Stand
Time
WL -0.03 (-0.81,0.76) -- -0.21 (-1.04,0.62) --
PT -0.6 (-1.15,-0.04) -0.57 (-1.49,0.35), 0.22 -0.09 (-0.66,0.48) 0.12 (-0.86,1.1), 0.80
IBET 0.19 (-0.43,0.81) 0.22 (-0.75,1.18), 0.66 0.01 (-0.65,0.66) 0.21 (-0.81,1.24), 0.68
EP

30 Second Chair
Stand
WL 0.06 (-1.05,1.17) -- 0.56 (-0.43,1.55) --
PT -0.2 (-0.98,0.58) -0.26 (-1.57,1.05), 0.70 0.12 (-0.57,0.81) -0.44 (-1.6,0.71), 0.45
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IBET 0.62 (-0.26,1.5) 0.57 (-0.81,1.94), 0.42 0.95 (0.16,1.73) 0.38 (-0.83,1.6), 0.53
2 Minute March
AC

Test
WL -8.51 (-14.94,-2.08) -- -0.5 (-7.28,6.28) --
PT -0.33 (-4.88,4.22) 8.18 (0.62,15.74), 0.03 1.73 (-2.94,6.4) 2.23 (-5.72,10.18), 0.58
IBET -2.32 (-7.42,2.78) 6.19 (-1.73,14.12), 0.12 3.01 (-2.33,8.35) 3.51 (-4.86,11.89), 0.41
Timed Up and
Go
WL -0.15 (-1.23,0.93) -- 0.04 (-1.19,1.27) --
PT -0.56 (-1.32,0.21) -0.41 (-1.68,0.86), 0.53 -0.68 (-1.53,0.18) -0.71 (-2.16,0.73), 0.33
IBET -0.82 (-1.68,0.03) -0.68 (-2,0.65), 0.32 -1.56 (-2.53,-0.59) -1.6 (-3.12,-0.08), 0.04
Weekly Minutes
of Aerobic
Activity
 ACCEPTED MANUSCRIPT

WL -0.22 (-1.73,1.29) -- -1.68 (-3.37,0) --

PT 1.11 (0.04,2.17) 1.33 (-0.45,3.1), 0.14 0.76 (-0.43,1.9) 2.45 (0.45,4.44), 0.02
IBET 2.25 (1.04,3.46) 2.47 (0.61,4.33), 0.01 0.83 (-0.52,2.18) 2.52 (0.42,4.61), 0.02
Weekly Minutes
of Stretching
WL -0.47 (-1.5,0.57) -- -1.37 (-2.32,-0.43) --
PT 1.61 (0.89,2.33) 2.08 (0.87,3.3), 0.00 0.29 (-0.38,0.97) 1.67 (0.55,2.78), 0.00
IBET 0.84 (0.02,1.67) 1.31 (0.03,2.59), 0.04 0.59 (-0.18,1.36) 1.96 (0.79,3.13), 0.00

PT
Weekly Minutes
of
Strengthening
WL 0.47 (-0.67,1.61) -- -0.17 (-1.4,1.05) --

RI
PT 2.02 (1.21,2.82) 1.55 (0.22,2.88), 0.02 1.12 (0.25,2) 1.3 (-0.15,2.74), 0.08
IBET 1.08 (0.17,1.99) 0.61 (-0.79,2.01), 0.39 1.19 (0.2,2.17) 1.36 (-0.16,2.88), 0.08
Patient Global
Assessment of

SC
Change – Right
Knee
WL 0.15 (-0.38,0.69) -- -0.2 (-0.74,0.33) --
PT 1.43 (1.04,1.81) 1.27 (0.64,1.91), 0.00 0.63 (0.24,1.03) 0.83 (0.2,1.47), 0.01

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IBET 0.60 (0.17,1.03) 0.45 (-0.21,1.11), 0.18 0.75 (0.29,1.20) 0.95 (0.28,1.62), 0.00
Patient Global
AN
Assessment of
Change – Left
Knee
WL 0.07 (-0.52,0.65) -- -0.33 (-0.92,0.26) --
PT 1.03 (0.63,1.42) 0.96 (0.28,1.64), 0.00 0.34 (-0.08,0.77) 0.67 (-0.03,1.37), 0.06
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IBET 0.56 (0.11,1.01) 0.49 (-0.22,1.20), 0.17 0.82 (0.35,1.29) 1.15 (0.43,1.88), 0.00
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Appendix Table 4. Differences in Mean Changes Between IBET and PT and 95%
Confidence Intervals
Difference in Baseline to Difference in Baseline
4-Month vs. PT (95% CI), to 12-Month vs. PT (95%
Outcome p-value CI), p-value
WOMAC Total
Intention-to-Treat 0.67 (-2.23,3.56), 0.65 -1.04 (-4.13,2.05), 0.51
Multiple Imputation* 0.85 (-2.06,3.75), 0.57 -0.96 (-4.06,2.14), 0.54

PT
Per Protocol 1.3 (-1.9,4.5), 0.43 -1.13 (-4.49,2.23), 0.51
WOMAC Function
Intention-to-Treat 1.04 (-1.07,3.15), 0.33 -0.11 (-2.34,2.13), 0.93
Multiple Imputation 1.00 (-1.09,3.08), 0.35 -0.36 (-2.55,1.84), 0.75

RI
Per Protocol 1.41 (-0.92,3.73), 0.23 -0.17 (-2.58,2.23), 0.89
WOMAC Pain
Intention-to-Treat -0.47 (-1.20,0.26), 0.20 -0.45 (-1.18,0.27), 0.22

SC
Multiple Imputation -0.41 (-1.16,0.33), 0.28 -0.40 (-1.13,0.32), 0.27
Per Protocol -0.4 (-1.2,0.4), 0.33 -0.47 (-1.27,0.32), 0.24
PASE Total
Intention-to-Treat -13.77 (-29.73,2.19), 0.09 -0.09 (-14.41,14.23), 0.99
Multiple Imputation -13.74 (-29.76,2.27), 0.09 1.52 (-13.12,16.16), 0.84

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Per Protocol -11.24 (-28.97,6.49), 0.21 -0.39 (-15.74,14.96),0.96
PASE Leisure
AN
Intention-to-Treat -4.61 (-9.49,0.28), 0.06 -1.01 (-7.20,5.18), 0.75
Multiple Imputation -5.00 (-9.98,-0.03), 0.05 -1.12 (-7.06,4.82), 0.71
Per Protocol -4.57 (-10.02,0.87), 0.09 -0.39 (-7.12,6.34), 0.91
PASE Household
M

Intention-to-Treat -8.09 (-17.13,0.94), 0.08 -6.02 (-14.27,2.24), 0.15

Multiple Imputation -6.77 (-15.76,2.21), 0.14 -6.14 (-14.69,2.42), 0.16
Per Protocol -7.97 (-17.77,1.82), 0.11 -6.5 (-15.46,2.46), 0.15
PASE Work
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Intention-to-Treat -2.98 (-13.45,7.49), 0.58 7.87 (-1.79,17.53), 0.11

Multiple Imputation -2.77 (-13.58,8.04), 0.62 8.63 (-0.73,17.99), 0.07
Per Protocol -1.38 (-13.1,10.34), 0.82 7.11 (-3.12,17.34), 0.17
TE

Unilateral Stand Time

Intention-to-Treat 0.61 (-0.16,1.38), 0.12 0.00 (-0.78,0.77), 1.00
Multiple Imputation 0.61 (-0.20,1.43), 0.14 0.04 (-0.72,0.80), 0.92
Per Protocol 0.79 (-0.01,1.58), 0.05 0.09 (-0.74,0.92), 0.83
EP

30 Second Chair Stand

Intention-to-Treat 0.63 (-0.40,1.66), 0.23 0.74 (-0.17,1.64), 0.11
Multiple Imputation 0.73 (-0.30,1.75), 0.16 0.73 (-0.17,1.64), 0.11
Per Protocol 0.82 (-0.3,1.95), 0.15 0.83 (-0.16,1.82), 0.10
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2 Minute March Test

Intention-to-Treat -2.86 (-8.94,3.21), 0.35 0.01 (-6.40,6.42), 1.00
Multiple Imputation -2.52 (-8.47,3.43), 0.41 0.29 (-6.34,6.92), 0.93
AC

Per Protocol -1.99 (-8.5,4.52), 0.55 1.28 (-5.53,8.1), 0.71

Timed Up and Go
Intention-to-Treat -0.24 (-1.23,0.74), 0.63 -0.72 (-1.85,0.41), 0.21
Multiple Imputation -0.34 (-1.40,0.73), 0.53 -0.53 (-1.69,0.62), 0.36
Per Protocol -0.27 (-1.35,0.82), 0.63 -0.89 (-2.13,0.36), 0.16
Weekly Minutes of Aerobic
Activity**
Intention-to-Treat 0.79 (-0.62,2.2), 0.27 -0.07 (-1.69,1.54), 0.93
Multiple Imputation 0.9 (-0.57,2.37), 0.23 -0.02 (-1.67,1.63), 0.98
Per Protocol 1.15 (-0.38,2.67), 0.14 0.07 (-1.66,1.8), 0.93
 ACCEPTED MANUSCRIPT

Weekly Minutes of Stretching**

Intention-to-Treat -0.48 (-1.46,0.5), 0.33 0.45 (-0.44,1.34), 0.32
Multiple Imputation -0.37 (-1.37,0.63), 0.46 0.44 (-0.49,1.37), 0.35 *Mul
Per Protocol -0.77 (-1.82,0.28), 0.15 0.3 (-0.67,1.27), 0.55 tiple
Weekly Minutes of Strengthening**
Impu
Intention-to-Treat -0.51 (-1.6,0.58), 0.36 0.14 (-1.03,1.31), 0.81
Multiple Imputation -0.38 (-1.47,0.72), 0.50 0.15 (-1.05,1.34), 0.81 tatio
Per Protocol -0.94 (-2.09,0.21), 0.11 0.07 (-1.19,1.32), 0.92 n

PT
Patient Global Assessment of was
Change – Right Knee
perf
Intention-to-Treat -0.93 (-1.44,-0.42), 0.00 -0.05 (-0.58,0.48), 0.85
Multiple Imputation -0.92 (-1.45,-0.4), 0.00 -0.07 (-0.6,0.46), 0.80 orme

RI
Per Protocol -0.83 (-1.38,-0.28), 0.00 0.12 (-0.46,0.69), 0.69 d on
missi
Patient Global Assessment of
ng
Change – Left Knee

SC
Intention-to-Treat -0.47 (-0.99,0.05), 0.07 0.39 (-0.18,0.97), 0.17 value
Multiple Imputation -0.45 (-0.99,0.09), 0.10 0.43 (-0.13,0.98), 0.13 s
Per Protocol -0.47 (-1.04,0.1), 0.10 0.48 (-0.13,1.08), 0.12 unde
r the Intention-to-Treat paradigm.

U
** A square root transformation was applied due to superior diagnostics in statistical models.
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Table 1. Participant Characteristics at Baseline*

Internet-Based
All Participants Exercise Training Physical Therapy Wait List Control
Characteristic (N=350) Group (N=142) Group (N=140) (N=68)
Age, years 65.3 (11.1) 65.3 (11.5) 65.7 (10.3) 64.3 (12.2)
Women N (%) 251 (71.7%) 98 (69%) 100 (71.4%) 53 (77.9%)

PT
Non-White Race N (%) 95 (27.4%) 48 (33.8%) 29 (21%) 18 (26.9%)
Married or Living with Partner N (%) 215 (61.4%) 93 (65.5%) 80 (57.1%) 42 (61.8%)
Bachelors Degree N (%) 208 (59.4%) 80 (56.3%) 86 (61.4%) 42 (61.8%)

RI
Employed N (%) 141 (40.3%) 51 (35.9%) 59 (42.1%) 31 (45.6%)
Household Financial Status: Low

SC
Income N (%) 62 (17.8%) 29 (20.6%) 20 (14.3%) 13 (19.1%)
Fair or Poor Health N (%) 48 (13.7%) 22 (15.5%) 14 (10%) 12 (17.6%)

U
2
Body Mass Index, kg/m 31.4 (8) 31.5 (7.8) 31.9 (8.6) 30.1 (7.3)
Joints with OA Symptoms 5.4 (3.2) 5.2 (3.1) 5.5 (3) 5.5 (3.9)

AN
Duration of OA Symptoms, years 13.1 (11.7) 11.6 (11) 14.1 (11.6) 14.2 (13)
PHQ-8 Score 3.8 (4.1) 3.7 (4.1) 4 (4.5) 3.6 (3.5)

M
WOMAC Total 32.0 (17.9) 31.3 (17.5) 32 (17.7) 33.6 (19.2)
WOMAC Pain Subscale 6.1 (3.8) 6.0 (3.9) 6.1 (3.5) 6.2 (4.0)

D
WOMAC Function Subscale 22.5 (13.0) 21.8 (12.7) 22.6 (12.9) 23.9 (13.8)

TE
PASE Total Score 126.9 (72.7) 132.3 (71.2) 121.4 (72) 126.9 (77.2)
PASE Household Score 75.2 (40.7) 81.6 (41.3) 70.4 (40.4) 71.8 (38.8)
PASE Leisure Score 21.6 (21.9) 22.4 (21.9) 20.9 (23.2) 21.5 (19.7)
EP
PASE Work Score 30.7 (51.1) 30.5 (51.5) 29.1 (48.4) 34.2 (55.9)
Timed Up and Go, seconds 11.9 (4.3) 12 (4.6) 11.9 (4.2) 11.6 (3.7)
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Unilateral Stand Test, seconds 7.2 (3.6) 7.3 (3.5) 7.3 (3.6) 6.7 (3.7)
AC

30 Second Chair Stand 9.5 (3.9) 9.5 (3.8) 9.5 (4.2) 9.6 (3.5)
PHQ = Patient Health Questionnaire, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index; PASE =
Physical Activity Scale for the Elderly. *Values are Mean (SD) unless otherwise specified.
Missing Data: non-white race = 3, household financial status = 1, WOMAC=2, Timed Up and Go =4 , PASE total = 10, PASE
Household = 5, PASE work = 1, PASE Leisure = 6
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Table 2. Within- and Between-Group Mean Changes in Outcomes and 95% Confidence Intervals:
Results of Intention-to-Treat Analyses
Baseline to 4- Difference in Baseline to Baseline to 12- Difference in Baseline
Month Difference 4-Month vs. WL (95% CI), Month Difference to 12-Month vs. WL
Outcome (95% CI) p-value (95% CI) (95% CI), p-value
WOMAC Total
(N=348)*
WL -3.37 (-6.33,-0.41) -- -2.83 (-5.93,0.27) --

PT
PT -6.73 (-8.86,-4.6) -3.36 (-6.84,0.12), 0.06 -4.42 (-6.66,-2.17) -1.59 (-5.26,2.08), 0.39
IBET -6.06 (-8.29,-3.84) -2.70 (-6.24,0.85), 0.14 -5.46 (-7.82,-3.09) -2.63 (-6.37,1.11), 0.17
WOMAC Function
(N=348)

RI
WL -2.3 (-4.46,-0.14) -- -1.51 (-3.76,0.74) --
PT -4.77 (-6.32,-3.23) -2.48 (-5.02,0.07), 0.06 -3.3 (-4.91,-1.68) -1.79 (-4.45,0.87), 0.19
IBET -3.74 (-5.36,-2.12) -1.44 (-4.03,1.15), 0.27 -3.4 (-5.11,-1.7) -1.90 (-4.61,0.82), 0.17

SC
WOMAC Pain
(N=350)
WL -0.66 (-1.41,0.09) -- -0.64 (-1.38,0.09) --
PT -1.11 (-1.65,-0.58) -0.45 (-1.33,0.42), 0.31 -0.7 (-1.23,-0.16) -0.05 (-0.92,0.81), 0.90
IBET -1.59 (-2.15,-1.02) -0.93 (-1.82,-0.03),0.04 -1.15 (-1.71,-0.59) -0.51 (-1.39,0.38), 0.26

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PASE Total
(N=340)
AN
WL -4.7 (-21.04,11.64) -- 1.17 (-13.11,15.45) --
PT 2.25 (-9.18,13.68) 6.95 (-12.31,26.22) ,0.48 8.28 (-2.01,18.56) 7.11 (-9.69,23.91), 0.41
IBET -11.52 (-23.79,0.74) -6.82 (-26.55,12.91), 0.50 8.19 (-2.99,19.37) 7.02 (-10.31,24.35), 0.43
PASE Leisure
M

(N=344)
WL -2.41 (-7.49,2.66) -- -0.11 (-6.25,6.04) --
PT 3.27 (-0.28,6.82) 5.68 (-0.25,11.62), 0.06 8.68 (4.3,13.05) 8.78 (1.46,16.1), 0.02
IBET -1.34 (-5.14,2.46) 1.07 (-5.70, 0.14), 0.73 7.66 (2.94,12.39) 7.77 (0.25,15.29), 0.04
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PASE Household
(N=345)
WL -5.32 (-14.49,3.84) -- -3.42 (-11.59,4.75) --
TE

PT -1.07 (-7.50,5.36) 4.25 (-6.59,15.09), 0.44 2.3 (-3.61,8.21) 5.72 (-3.94,15.38), 0.25
IBET -9.16 (-16.11,-2.21) -3.84 (-14.99,7.31), 0.50 -3.72 (-10.13,2.69) -0.3 (-10.26,9.67), 0.95
PASE Work
(N=349)
EP

WL 2.35 (-8.45,13.15) -- 5.24 (-4.49,14.98) --

PT 0.98 (-6.53,8.48) -1.37 (-14.12,11.37), 0.83 -2.62 (-9.58,4.34) -7.86 (-19.36,3.63), 0.18
IBET -2.00 (-10.01,6) -4.35 (-17.39,8.69), 0.51 5.25 (-2.2,12.69) 0.00 (-11.78,11.79), 1.00
Unilateral Stand
C

Time (N=350)
WL 0.04 (-0.75,0.82) -- -0.09 (-0.88,0.69) --
AC

PT -0.59 (-1.15,-0.03) -0.63 (-1.56,0.30), 0.19 -0.05 (-0.6,0.50) 0.04 (-0.89,0.98), 0.93
IBET 0.02 (-0.57,0.61) -0.02 (-0.97,0.93), 0.97 -0.05 (-0.64,0.53) 0.04 (-0.91,1.00), 0.93
30 Second Chair
Stand (N=350)
WL 0.18 (-0.87,1.23) -- 0.66 (-0.27,1.58) --
PT -0.13 (-0.87,0.61) -0.31 (-1.55,0.94), 0.63 0.16 (-0.49,0.82) -0.49 (-1.58,0.60), 0.37
IBET 0.50 (-0.29,1.28) 0.32 (-0.95,1.59), 0.62 0.90 (0.20,1.60) 0.24 (-0.87,1.35), 0.67
2 Minute March
Test (N=350)
WL -8.43 (-14.61,-2.24) -- 0.00 (-6.49,6.48) --
PT -0.68 (-5.07,3.71) 7.75 (0.43,15.07), 0.04 1.11 (-3.45,5.67) 1.12 (-6.59,8.82), 0.78
IBET -3.54 (-8.20,1.11) 4.88 (-2.56,12.33), 0.20 1.12 (-3.76,6) 1.13 (-6.74,8.99), 0.78
 ACCEPTED MANUSCRIPT

Timed Up and Go
(N=346)
WL -0.23 (-1.24,0.78) -- -0.26 (-1.4,0.87) --
PT -0.62 (-1.34,0.09) -0.39 (-1.58,0.8), 0.52 -0.77 (-1.57,0.04) -0.5 (-1.86,0.85), 0.46
IBET -0.87 (-1.63,-0.11) -0.64 (-1.85,0.58), 0.30 -1.49 (-2.35,-0.63) -1.22 (-2.61,0.16), 0.08
Weekly Minutes of
Aerobic Activity**
WL -0.09 (-1.53,1.35) -- -1.59 (-3.21,0.04) --

PT
PT 1 (-0.02,2.02) 1.09 (-0.61,2.8), 0.21 0.48 (-0.67,1.63) 2.07 (0.13,4), 0.04
IBET 1.79 (0.71,2.88) 1.89 (0.15,3.62), 0.03 0.41 (-0.82,1.63) 1.99 (0.01,3.97), 0.05
Weekly Minutes of
Stretching**

RI
WL -0.4 (-1.39,0.6) -- -1.34 (-2.24,-0.44) --
PT 1.45 (0.76,2.15) 1.85 (0.67,3.03), 0.00 0.27 (-0.37,0.92) 1.62 (0.55,2.68), 0.00
IBET 0.97 (0.23,1.72) 1.37 (0.16,2.57), 0.03 0.72 (0.04,1.41) 2.07 (0.98,3.16), 0.00
Weekly Minutes of

SC
Strengthening**
WL 0.43 (-0.69,1.54) -- -0.14 (-1.32,1.04) --
PT 1.78 (0.99,2.57) 1.36 (0.05,2.66), 0.04 1.07 (0.23,1.91) 1.21 (-0.18,2.6), 0.09
IBET 1.27 (0.44,2.11) 0.85 (-0.49,2.19), 0.22 1.21 (0.32,2.1) 1.35 (-0.08,2.78), 0.06

U
Patient Global
Assessment of
AN
Change – Right
Knee
WL 0.15 (-0.36,0.66) -- -0.18 (-0.69,0.33) --
PT 1.36 (0.99,1.73) 1.21 (0.6,1.81), 0.00 0.58 (0.2,0.96) 0.76 (0.15,1.37), 0.01
IBET 0.42 (0.03,0.82) 0.27 (-0.35,0.89), 0.39 0.53 (0.12,0.94) 0.71 (0.08,1.33), 0.03
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Patient Global
Assessment of
Change – Left
D

Knee
WL -0.09 (-0.64,0.45) -- -0.38 (-0.95,0.19) --
PT 0.93 (0.56,1.31) 1.03 (0.39,1.66), 0.00 0.17 (-0.24,0.59) 0.56 (-0.12,1.23), 0.11
TE

IBET 0.46 (0.06,0.86) 0.56 (-0.1,1.21), 0.09 0.57 (0.13,1.01) 0.95 (0.26,1.64), 0.01
*Indicates number included in the statistical model for that outcome.
** A square root transformation was applied due to superior diagnostics in statistical models.
Notes: Between-group comparisons refer to changes from baseline for each intervention group relative to the WL group.
EP

Results are least-squares means and mean differences (and corresponding 95% confidence intervals) from separate
general linear mixed effects models, as described in the Methods.
WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index; PASE = Physical Activity Scale for the Elderly
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Table 3. Standardized Mean Differences and 95% Confidence

Intervals (CIs) for IBET and PT vs. WL Control Group

Outcome 4 Months 12 Months

WOMAC Total
PT -0.26 (- 0.53, 0.00) -0.12 (-0.40, 0.16)
IBET -0.20 (- 0.48, 0.07) -0.19 (-0.46, 0.09)

PT
WOMAC Function
PT -0.27 (-0.52, -0.01) -0.19 (-0.45, 0.08)
IBET -0.15 (-0.43, 0.13) -0.19 (-0.45, 0.08)
WOMAC Pain

RI
PT -0.14 (-0.39, 0.11) -0.02 (-0.31, 0.27)
IBET -0.28 (-0.41, -0.15) -0.15 (-0.39, 0.09)

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Identified from
Identified from
Self-Referrals Johnston County
UNC Medical
(SR) Osteoarthritis Project
Records
n=158 (JoCo) Database
n=10,860
n=256

PT
Not Screened: n=4 Ineligible per Med Record
Ineligible per Not Screened: n=12
Review: n=304
Screener*: Ineligible per
Bad Contact Info: n=232
Screener*:

RI
n=33 Not Screened: n=8595
Refused: n=33 n=77
Ineligible per Screener*: n=158
Refused: n=102
Refused: n=1309

SC
Reasons for Ineligibility at
Screener (Total = 268)
No Knee OA = 88
No Internet Access = 64
Exclusionary Health

U
Condition = 48
Meeting Physical Activity
Total Screened Eligible: n=415
(SR: n=88, UNC: n=262, JoCo: n=65) Refused n=65
Recommendations = 13
AN
Had Joint Replacement
Surgery = 10
Not English Speaker = 10
Deceased = 10
Receiving PT for OA = 7 Total Enrolled and Randomized: n=350
(SR: n=72, UNC: n=224, JoCo: n=54)
M

Moved Out of Area = 6

In Another OA Study = 5
Missing Data = 7
D

PT Group: IBET Group: Waitlist Control:

n=140 n=142 n=68
TE

Dropped: n=4 Dropped: n=5 Dropped: n=0

Withdrew: n=0 Withdrew: n=13 Withdrew: n=1
Missed Visit: n=6 Missed Visit: n=8 Missed Visit: n=3
EP

Lost to Follow Up: Lost to Follow Up: Lost to Follow Up:

n=0 n=2 n=3
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4 Month Follow - 4 Month Follow - 4 Month Follow -

Up Completed: Up Completed: Up Completed:
n=130 n=114 n=61
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Dropped: n=3 Dropped: n=5 Dropped: n=1

Withdrew: n=0 Withdrew: n=1 Withdrew: n=0
Missed Visit: n=0 Missed Visit: n=0 Missed Visit: n=0
Lost to Follow Up: Lost to Follow Up: Lost to Follow Up:
n=3 n=5 n=0

12 Month Follow 12 Month Follow 12 Month Follow

Up Completed: Up Completed: Up Completed:
n=129 n=112 n=63

Figure 1: CONSORT Diagram

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PT
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Figure 2. Estimated mean WOMAC Total Scores and 95% Confidence Intervals by
Group and Time Point
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PT
RI
U SC
AN
Figure 3. Comparison of Change in WOMAC Total Scores between IBET and PT
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Group (Non-Inferiority Hypotheses): Results of Intent-to-Treat Analyses

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