Conditions: Osteoarthritis Osteo Arthritis Knee
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 120
Healthy volunteers: no

Brief summary:
This prospective, double-blinded, placebo-controlled, randomized trial will enroll 120 SKOA subjects at the NYU Center for Musculoskeletal Care. Patients meeting entry criteria will be randomized 1:1 to treatment with colchicine or placebo daily for 3 months. Subjects will have detailed evaluation of standardized clinical pain outcomes, candidate peripheral blood biomarkers, baseline knee radiographs as well as MSK-US, and a subset will undergo evaluation of their synovial fluid.

Detailed description:

Arms:
arm 1: Placebo in capsule identical to study drug arm 2: 0.6 or 0.8 mg orally once daily.

Because recent studies suggest that a dose of 0.6mg may be sufficient for chronic inflammatory suppression and may reduce the already low risk of toxicity of 0.8mg, for the remainder (second half) of the study the dosage will be switched from 0.8mg to a 0.6mg dose to allow comparison of the two doses.

Interventions: intervention 1: Colchicine 0.8 mg or 0.6 mg orally once daily intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Colchicine 0.8 mg orally once daily for 1.5 months, and then 0.6 mg once daily for the remainder of the time (1.5 months) intervention 2: Placebo 0.8 mg or 0.6 mg orally once daily for 3 months

Protocol document:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Colchicine for the Treatment of Osteoarthritis of the Knee (CLOAK) 
 
A Phase II, Randomized, Double-Blind, Placebo-Controlled, Single-
Center Study of the Effects of Colchicine on Pain and Inflammation in 
Subjects with Knee Osteoarthritis. 
NCT Number: 
NCT03913442 
Study Number: 
 
 s16-01796 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
July 25, 2023 
 
 


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Colchicine for the Treatment of Osteoarthritis of the Knee (CLOAK) 
 
A Phase II, Randomized, Double-Blind, Placebo-Controlled, Single-Center Study 
of the Effects of Colchicine on Pain and Inflammation in Subjects with Knee 
Osteoarthritis. 
 
 
Regulatory Sponsor: 
NYU Langone Health 
Division of Rheumatology, Department of Medicine 
333 East 38th Street 
New York, NY 10016 
646-501-7400 
 
Funding Sponsor: 
Rheumatology Research Foundation 
2200 Lake Blvd., NE  
Atlanta, GA   30319 
404-633-3777  
 
Hikma Pharmaceuticals USA Inc. 
246 Industrial Way West 
Eatontown, NJ 07724 
 
Future manufacturing site of the drug product: 
Hikma Pharmaceuticals 
1809 Wilson Road 
Columbus, OH 43228 
 
 
Study Product: 
Colchicine  
Protocol Number: 
s16-01796 
IND Number: 
143204 
 
 
Initial version: 
3/22/2019 
Amended: 
7/23/2019                                                            
Amended:           3/27/2020 
Amended:  
9/9/2020 
Amended:  
10/19/2020 
Amended:  
7/12/2021 
Amended:           8/19/2021 
Amended:           11/22/2021 
Amended:           12/21/2021 
 
 
 
 
 
 
 
7/25/2023 
Amended:  
2/15/2022 
Amended:  
3/23/2022 
Amended: 
4/06/2022 
Clinical Research Protocol 


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Table of Contents 
 
OARSI:  
 Osteoarthritis Research Society International ................................................................... 4 
STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION .................................................................................................................................. 6 
1.1 
BACKGROUND ................................................................................................................................ 6 
1.2  
INVESTIGATIONAL AGENT ................................................................................................................ 9 
TABLE 3 DOSE AND EXPOSURE .................................................................................................................... 9 
1.3 
PRECLINICAL DATA ........................................................................................................................ 9 
1.4 
CLINICAL DATA TO DATE............................................................................................................... 10 
1.5 
DOSE RATIONALE ......................................................................................................................... 11 
1.6 
RESEARCH RISKS & BENEFITS ...................................................................................................... 11 
1.6.1 
Risk of Study Drug ................................................................................................................ 11 
1.6.2 
Other Risks of Study Participation ......................................................................................... 11 
1.6.3 
Potential benefits ................................................................................................................... 13 
2 
STUDY OBJECTIVES ....................................................................................................................... 13 
3 
STUDY DESIGN ................................................................................................................................. 15 
3.1 
GENERAL DESIGN ........................................................................................................................ 15 
3.2 
PRIMARY STUDY ENDPOINTS ........................................................................................................ 15 
3.3 
SECONDARY STUDY ENDPOINTS ................................................................................................... 15 
3.4 
PRIMARY SAFETY ENDPOINTS ....................................................................................................... 16 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 16 
4.1 
INCLUSION CRITERIA .................................................................................................................... 16 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 17 
4.3 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 18 
4.4 
EARLY WITHDRAWAL .................................................................................................................... 19 
4.4.1 
When and How to Withdraw Subjects ................................................................................... 20 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 20 
5 
STUDY DRUG .................................................................................................................................... 21 
5.1 
DESCRIPTION ............................................................................................................................... 21 
5.2 
TREATMENT REGIMEN .................................................................................................................. 21 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 21 
5.4 
PREPARATION, STORAGE AND ADMINISTRATION OF STUDY DRUG .................................................. 21 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 21 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 21 
5.7 
GENERAL METHOD OF PREPARATION AND PACKAGING ................................................................... 22 
5.8 
DRUG COMPONENTS AND DRUG PRODUCT ................................................................................... 23 
5.9 
BLINDING OF STUDY DRUG ........................................................................................................... 25 
5.10 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 25 
5.10.1 
Receipt of Drug Supplies .................................................................................................. 25 
5.10.2 
Storage .............................................................................................................................. 25 
5.10.3 
Dispensing of Study Drug ................................................................................................. 25 
5.10.4 
Return or Destruction of Study Drug ................................................................................. 26 
6 
STUDY PROCEDURES ..................................................................................................................... 26 
6.1 
BASELINE (WINDOW) .................................................................................................................... 26 
6.2 
VISIT 1 (WEEK 6/ DAY 42) ............................................................................................................ 27 
6.3 
VISIT 3 (WEEK 16/DAY 112) ......................................................................................................... 27 


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7 
STATISTICAL PLAN ......................................................................................................................... 29 
7.1 
STATISTICAL METHODS ................................................................................................................ 29 
7.2 
SAMPLE SIZE DETERMINATION ...................................................................................................... 29 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 30 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 30 
8.1 
DEFINITIONS ................................................................................................................................ 30 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 32 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 32 
8.3.1 
Investigator reporting: notifying the study sponsor ................................................................ 33 
8.3.2 
Investigator reporting: notifying the IRB ................................................................................ 33 
8.3.3 
Sponsor reporting: Notifying the FDA ................................................................................... 34 
8.4 
UNBLINDING PROCEDURES ........................................................................................................... 35 
8.5 
STOPPING RULES ......................................................................................................................... 35 
8.6 
MEDICAL MONITORING ................................................................................................................. 35 
8.6.1 
Data Monitoring Committee ................................................................................................... 36 
9 
SAMPLE STORAGE, DATA HANDLING, AND RECORD KEEPING .............................................. 36 
9.1 
CONFIDENTIALITY ......................................................................................................................... 36 
9.2 
CONFIDENTIALITY AND HIPAA ...................................................................................................... 37 
9.3 
SOURCE DOCUMENTS .................................................................................................................. 37 
9.4 
CASE REPORT FORMS ................................................................................................................. 37 
9.5 
RECORDS RETENTION .................................................................................................................. 37 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 38 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 38 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 38 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 38 
12 
STUDY FINANCES ............................................................................................................................ 39 
12.1 
FUNDING SOURCE ........................................................................................................................ 39 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 39 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 39 
13 
PUBLICATION PLAN ........................................................................................................................ 39 
14 
REFERENCES ................................................................................................................................... 39 
15 
APPENDICIES ................................................................................................................................... 41 
 
 
 


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List of Abbreviations 
 
 
AE: 
 
 
Adverse Event 
BMI: 
 
 
Body Mass Index 
CMC:   
 
Center for Musculoskeletal Care 
CPP:   
 
Calcium Pyrophosphate 
CPPD:  
 
Calcium Pyrophosphate Deposition Disease 
CRF: 
 
 
Case Report Form 
CV: 
 
 
Cardiovascular 
DMOADs:  
 
Disease Modifying Osteoarthritis Drugs 
DSMC:  
 
Data Safety Monitoring Committee 
eCRF:  
 
Electronic Case Report Form 
eGFR:   
 
Estimated Glomerular Filtration Rate  
FDA: 
 
 
Food and Drug Administration 
FMF:    
 
Familial Mediterranean Fever 
hsCRP:  
 
Highly Sensitive C-Reactive Protein  
IL-1Ra:  
 
IL-1 Receptor Antagonist 
IMD:  
 
 
Intermargin Distance 
IND: 
 
 
Investigational New Drug Application 
iNOS:   
 
Nitric Oxide Synthetase  
JNS: 
 
 
Joint Space Narrowing 
JSW:   
 
Joint Space Width 
KL:  
 
 
Kellgren and Lawrence Scoring System 
KOOS:  
 
Knee injury and Osteoarthritis Outcome Score 
MDRD Equation: 
Modification of Diet in Renal Disease 
MTP: 
 
 
Medial Tibial Plateau  
MSK-US:  
 
Musculoskeletal Ultrasound 
MSU: 
 
 
Monosodium Urate 
NIH:  
 
 
National Institutes of Health 
NO:  
 
 
Nitric Oxide 
NYC: 
 
 
New York City 
NSAIDs:  
 
Non-Steroidal Anti-Inflammatory Drugs 
OA:  
 
 
Osteoarthritis 
OARSI:  
 
Osteoarthritis Research Society International 
PA:  
 
 
Posterior/Anterior 
PBL:  
 
 
Peripheral Blood Leukocyte 
PI: 
 
 
Principal Investigator 
SAE:   
 
Serious Adverse Event 
SF36:   
 
Short Form Health Survey 
SKOA:   
 
Symptomatic Knee Osteoarthritis  
US:  
 
 
United States 
USA:   
 
United States of America 
VAS: 
 
 
Visual Analog Scale 
WOMAC:  
 
Western Ontario and McMaster Universities Arthritis Index 
 
 
 
 
 
 
 
 


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Study Summary 
Title 
Colchicine for the Treatment of Osteoarthritis of the Knee: A Phase II, 
Randomized, Double-Blind, Placebo-Controlled, Single-Center Study of 
the Effects of Colchicine on Pain and Inflammation in Subjects with 
Knee Osteoarthritis.  
Short Title 
CLOAK 
Protocol Number 
 s16-01796 
Phase 
Phase 2 
Methodology 
Double blind, randomized, placebo controlled 
Study Duration 
Estimated duration for the main protocol (e.g. from start of screening to last 
subject processed and finishing the study) – 36 months 
Study Center(s) 
Single-center  
Objectives 
To investigate whether colchicine has utility in the treatment of knee OA pain, 
and in the modulation of both blood-based and imaging biomarkers that may 
associate with symptomatic and structural progression of knee OA.    
Number of Subjects 
120 
Diagnosis and Main 
Inclusion Criteria 
Subjects must have symptomatic and radiographic knee OA 
Study Product, Dose, 
Route, Regimen 
Colchicine 0.8 mg or 0.6 mg orally once daily 
Duration of 
administration 
90 days 
Reference therapy 
Placebo in capsule identical to study drug 
Statistical 
Methodology 
The following will be used where appropriate: descriptive statistics, tests of 
normality of continuous outcome measurements, T-tests or Wilcoxon 
nonparametric counterpart, chi-square (Fisher exact) test to compare 
proportions of outcomes between groups, multivariate linear (logistic) 
regression methods with adjustment of potential confounding variables. When 
multiple time points are considered such as at baseline, 1, 2 and 3 months, 
we will model linear trajectories of outcome scores across time using mixed-
effects regression models. The models will be specified with random 
intercepts and slopes such that a linear trajectory representing outcome 
scores will be compared between treatment groups. 
 


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1 
Introduction 
 
This document is a protocol for a human research study. This study is to be conducted in accordance with 
US government research regulations, and applicable international standards of Good Clinical Practice, 
and institutional research policies and procedures. 
 
Our project seeks to investigate whether colchicine, an already FDA-approved treatment for gout, has utility 
in osteoarthritis (OA). OA is the most common arthritis, with more than 30 million people affected in the 
United States. OA can be painful, debilitating and may even shorten life expectancy. Unfortunately, 
approved drug treatments are only analgesic, and for many patients work poorly and/or are poorly tolerated 
(indeed, recent data suggests that acetaminophen, the first line therapy for OA, is essentially ineffective). 
There are no drugs approved in the US to actually slow down the progression of OA. OA processes are 
beginning to be better understood, and it is now appreciated that local inflammation is likely to play a role 
in OA joint pain, impairment of joint function, and the health of joint cells including cartilage cells 
(chondrocytes) and synovial cells, whose proper function is essential to maintaining joint health. We and 
others have reported that local OA inflammation can actually be detectible systemically through biomarkers 
in the blood of some OA patients, and that in those patients OA may progress faster. In this project we 
propose to test an anti-inflammatory drug known as colchicine, which has been in use for more than 2,000 
years for gout and other inflammatory disorders. At low doses colchicine is well tolerated, and preliminary 
evidence suggests that colchicine 1) targets some of the processes now appreciated to play a role in OA, 
and 2) may have a positive impact on OA pain. We will enroll patients with knee OA, already accessible to 
us from a previous study (Leukocyte Gene Expression in Osteoarthritis, LGEO), along with information 
collected from that study, and treat them with colchicine or placebo daily. In addition to measuring impact 
on pain and function, we will measure colchicine’s impact on markers of inflammation, in both the blood 
and the joint fluid (including uric acid levels as a novel biomarker of serum and synovial fluid). We will use 
imaging to assess the impact of colchicine on inflammatory synovitis within the joints. If successful, our 
studies could identify a new (old!) drug as a potential treatment for OA, and perhaps as a potential agent 
than can actually alter OA biology. If colchicine is effective on some but not all outcomes, that will still be a 
potential major treatment advance.  Even if colchicine does not improve OA status, the intensive 
assessment that is intrinsic to the trial will extend our prior, NIH-funded study of OA natural history, and 
provide important insights into OA biomarkers and progression. 
1.1 
Background 
 
Osteoarthritis (OA): Scope of the Problem: OA affects more than 30 million adults in the USA (1, 2), yet 
disease modifying OA drugs (DMOADs) are currently lacking. Few randomized controlled trials have 
assessed the effect of medications on both symptom and structure modification, based upon proposed OA 
pathologic mechanisms, and none have shown unequivocal success.  
 
OA as an Inflammatory Disease: We and others have shown that OA is locally, and perhaps systemically 
inflammatory (3-7). Synovitis is present (7,8), and cytokines including IL-1β and TNF-α can be detected in 
the synovial fluid and peripheral blood of patients with OA joint degeneration (4,9). Furthermore, our 
analyses of peripheral blood leukocyte (PBL) gene expression profiles have identified a subset of 
symptomatic knee OA (SKOA) patients, whose increased expression of mRNA for IL-1β, TNF-α, and COX-
2 is associated with increased pain and risk for radiographic progression at 24 months (Tables 1     
and 2)(4). We have also shown in multiple cohorts that the pro-inflammatory lipids PGE2 and 15-HETE 
   
 
 
 
 
 
 
 
 


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are detectable in the plasma of ~40% of SKOA patients, and are similarly associated with OA disease 
severity (10). Most recently, we found that plasma levels of IL-1Ra (IL-1 receptor antagonist) are 
independently associated with SKOA severity and progression (11). Taken together, these findings suggest 
that there is chronic low-grade inflammation in SKOA, and that at least some soluble and cellular markers 
of OA joint inflammation can be detected in peripheral blood. It is not surprising, then, that certain anti-
inflammatory strategies (e.g., steroid injections, NSAIDs) have some capacity for ameliorating OA 
symptoms, although these agents do not appear to affect OA structural outcomes (12). Given the 
prevalence, pain and disability of OA, and the current lack of adequate treatments, the possibility that other 
anti-inflammatory strategies might prove equally or ideally more effective for ameliorating OA symptoms, 
and certainly, the possibility that the “right” anti-inflammatory strategies might have disease modifying 
activities, deserves serious consideration. 
 
 
 
  
A Role for Crystals in OA? Clinicians have long assumed an association between crystal arthropathies and 
OA presence, but investigations assessing a clinical, or indeed a pathogenic relationship between crystals 
and OA are few and far between. Crystal-induced mechanical cartilage damage could theoretically 
stimulate OA progression; in this regard it is relevant that OA and gout or chondrocalcinosis frequently co-
occur (13). Muehlemann et al investigated the prevalence of monosodium urate (MSU) and calcium 
pyrophosphate (CPP) crystals in 7855 cadaveric tali. The presence of crystals was strongly associated with 
cartilage lesions that seemed to be biomechanically induced. Strikingly, however, only 34% of crystals 
detected were CPP; the remaining 66% composed of MSU, suggesting a role for MSU crystals even in the 
absence of clinical gout (14). Indeed, in ultrasound studies from our group and others, MSU crystals on 
cartilage can be detected in a significant percentage of patients with asymptomatic hyperuricemia, and 
even occasionally in patients with neither hyperuricemia nor gout (15). In addition to biomechanically-
induced cartilage damage leading to OA, MSU and other crystals might act biochemically, biophysically or 
via receptor (e.g., Toll-like Receptor 4) interactions to induce chondrocyte and/or synoviocyte activation, 
leading to OA. In gout and pseudogout, the concept of MSU crystals mediating joint inflammation is well 
established. In particular, MSU (and CPP) crystals promote the release of IL-1β and IL-18 via activation of 
the NLRP3 inflammasome (16). Despite the role of IL-1β in OA, it remains uncertain whether the IL-1β 
/inflammasome pathway contributes to the development of OA in joints affected by MSU-triggered 
inflammation. Supporting such a model, synovial fluid urate concentrations have recently been shown to 
correlate with synovial fluid IL-1β and IL-18, and with radiographic severity of knee OA (9), leading the 
investigators to propose that chondrocyte necrosis in early OA results in the release of urate as a “danger 
signal,” promoting IL-1β generation, additional inflammation, and further chondrocyte death. Other 
mechanisms could also play a role in the contribution of MSU deposition to OA. For example, Liu et al have 
demonstrated that MSU crystals can directly (i.e., independent of IL-1β) up-regulate inducible nitric oxide 
synthetase (iNOS), nitric oxide (NO) release and MMP-3 secretion, all mediators with potential roles in OA 
pathogenesis (17,18).  
 
 


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Our group has conducted a prospective pilot study to compare the prevalence of knee OA between gout, 
asymptomatic hyperuricemic and control subjects (19). 
Using standardized radiographs to assess for knee OA, 
and musculoskeletal ultrasound to assess for occult MSU 
deposition, we found a markedly increased prevalence and 
severity of knee OA in gout patients vs. non-hyperuricemic 
controls, and an intermediate prevalence and severity of 
knee OA in asymptomatic hyperuricemia patients (Figure 
2). Moreover, patients with MSU cartilage deposition on 
ultrasound were more likely to have knee OA than those 
without, regardless of gout versus hyperuricemic status. 
Interestingly, MSU deposition conveyed risk for knee OA 
even when the deposition was in OA-unaffected joints, 
suggesting the possibility of a metabolic or systemic 
inflammatory effect.  
 
More recently, we have taken the opposite approach, 
reviewing a group of patients with known medial knee OA 
for whom we had available standing knee X-rays at 
baseline and after two years. Using banked serum, we 
assessed patient baseline urate values and compared 
them with the degree of progression. Consistent with an 
interaction between urate and OA, we observed a direct 
correlation between baseline urate values and the degree of 
joint space narrowing (JSN) over the observation period 
(Figure 3). 
 
 
 
 
 
 
 
1.2  
Investigational Agent 
 
Colchicine, most commonly used to treat gout and calcium crystal-induced inflammation, is a generally safe 
and well-tolerated drug, with more than two thousand years of physician experience (20). Colchicine is a 
tricyclic, lipid-soluble alkaloid with a long terminal half-life (20 to 40 hours) and bioavailability ranging from 
24% to 88% (Figure 4).  Within the bloodstream, ~40% of colchicine binds to albumin. Although peak 
plasma concentrations occur 1 hour after administration, maximal anti-inflammatory effects develop over 
24 to 48 hours, based on leukocyte accumulation. Colchicine reaches much higher concentrations in 
leukocytes than in plasma, and persists there for several days after ingestion, with concentrations ranging 
from 4 to 64 ng/109.  Colchicine uptake into other cells has not been as rigorously defined, but evidence 
suggests that the drug also affects monocyte/macrophages and synovial fibroblasts. Whether colchicine 
directly affects chondrocytes has not been determined. 
 
 
Figure 4 Molecular Structure of Colchicine 
Figure 2. Prevalence of knee OA, and bilateral knee OA, among 
control, AH and gout groups. Subjects were assessed for presence 
of knee OA and/or bilateral knee OA using either ACR 
Clinical/Radiographic or ACR Clinical OA criteria, as indicated 
(*P<0.05 vs control group). 
Figure 3. Serum urate correlates with 24 
month joint space narrowing (JSN) in 
patients with established OA.  A, Scatter 
plot.  B, Serum urate arranged according to 
quartiles. 


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For this study we will be employing a non-standard dose of Colchicine, specifically 0.81 mg daily, 
compared to the FDA approved 0.6 mg dose.  The doses are between the minimum and maximum 
recommended daily dose of Colchicine (0.6-1.2mg).  For this study, Hikma Pharmaceuticals is 
formulating the 0.81 mg dose with the same capsule used for the standard daily dose 0.6 mg. The 
formulation of that capsule can be found in Table 3. 
 
Table 3 Dose and Exposure 
 
– 
Formulation and dose: 
Ingredient 
Mg/cap 
Colchicine, USP 
0.6 mg or 0.81mg1 
Microcrystalline Cellulose, NF (Avicel pH 101) 
5.65mg 
Anhydrous lactose, NF (Tablet Grade) 
101.77mg2 
Sodium Starch Glycolate, NF (Primojel) 
3.4mg 
Colloidal Silicon Dioxide, NF (Cab-o-sil) 
0.56mg 
Magnesium Stearate, NF 
1.13mg 
#4 Med Orange/Lt. Blue Hard Gelatin Capsules printed 
“Hikma Pharmaceuticals119” in white ink 
(40mg) 
Total Weight (Target Filled Capsule) 
153.32mg 
1Equivalent to 0.808mg/cap (1% excess based on Anhydrous, Solvent Free Basis, adjusted for assay, 
moisture content, and ethyl acetate. 
2Adjusted to make Total 113.32mg/cap 
– 
Route of Administration: Oral 
– 
Planned exposure (90 days) 
 
1.3 
Preclinical Data 
 
Colchicine inhibits microtubules and adhesion molecules in inflammatory cells, abrogating multiple 
processes that contribute to the production of catabolic mediators in the joint (21, 22). Colchicine inhibits 
neutrophil chemotaxis and lysosomal enzyme release (23). Colchicine modulates E- and L-selectin 
distribution and expression, impeding leukocyte-endothelial cell interactions (22). More recently it has been 
shown that colchicine also inhibits caspase-1 in the monocyte/macrophage NLRP3 inflammasome, thus 
blocking the conversion of pro-IL-1β to active IL-1β, mitigating the release of IL-1β and, secondarily, of 
TNFα and other inflammatory mediators that are also implicated in OA (16) (Figure 5). 
 
Colchicine is most commonly used to treat acute gouty flares, and as prophylaxis for gouty flares as well 
as for prophylaxis and acute treatment of calcium pyrophosphate crystal arthritis (i.e., pseudogout). It also 


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used in familial Mediterranean fever (FMF), some types of vasculitides and neutrophilic dermatoses, 
pericarditis, and more recently has been studied in coronary artery disease and atrial fibrillation. 
 
The apparent association between crystals and OA lends biologic plausibility to the possibility that 
colchicine, by diminishing inflammation, could be an effective treatment for OA. Figure 5 displays how 
colchicine’s mechanisms of action target several processes implicated in OA.  Importantly, colchicine 
warrants study even if crystals are not a driving factor in OA pathogenesis, given its ability to inhibit the 
production of cytokines and inflammatory markers that are known to be associated with OA joint pain and 
degeneration. Critical to this study, our group has had significant research expertise in studying 
inflammation and colchicine for many years. For 
example, in patients with gout, we are currently studying 
whether chronic colchicine use is associated with 
reduced rates of acute cardiovascular (CV) syndromes 
(24). We are also collaborating with our interventional 
cardiology colleagues to test whether cardiac patients 
who are given colchicine prior to percutaneous CV 
intervention experience reduced rates of post-procedure 
inflammation (a marker of poorer long-term outcomes), 
compared with patients who receive placebo. 
 
 
 
Figure 5. Inflammatory processes that contribute to OA 
pathogenesis and colchicine’s 
potential therapeutic targets therein. 
 
1.4 
Clinical Data to Date 
 
Colchicine is FDA-approved, in doses of 0.6 mgs once or twice daily, for long-term use in gout prophylaxis. 
In familial Mediterranean fever, colchicine is used at doses up to 1.8 mgs daily in divided doses, essentially 
for a lifetime. To date, three small, randomized controlled trials have assessed the potential for a symptom-
modifying effect of colchicine in knee OA (25,26,27). Aran et al examined physician and patient global 
assessment endpoints, using non-validated 15-point VAS scales, in 61 female patients, and found that 
patients receiving colchicine had improved assessment scores and approximately a 50% decrease in the 
use of breakthrough pain medication (acetaminophen) compared to placebo controls (25). Das et al studied 
the addition of colchicine to nimesulide (an NSAID) in 36 patients, and found significantly improved total 
WOMAC and VAS pain scores in the colchicine vs placebo groups (26). Das also examined the addition of 
colchicine to intra-articular steroids and piroxicam in 39 patients with clinical evidence of “inflammation” of 
the knee, of whom 38% had radiographic chondrocalcinosis and 74% had CPPD crystals on polarizing 
microscopy (27). They found a greater reduction in 15-point VAS pain and greater improvement in a 
modified WOMAC scale, in the group who received colchicine vs placebo.  
 
Limitations in the designs of the aforementioned studies, as well as the brief time frames of their study 
periods, underline the need for investigations incorporating rigorous methodology and validated outcome 
measures. Moreover, these prior studies did not address the cellular, inflammatory or structural impact of 
colchicine treatment. The possibility that a well-established, relatively safe, and FDA-approved drug might 
improve the management of a currently untreatable disease lends further urgency to the question. We 
therefore propose a double-blind, randomized controlled trial, to determine whether colchicine treatment 
can: 
- 
improve pain, function, and quality of life in SKOA patients  
- 
improve inflammatory PBL, plasma, and synovial fluid markers in SKOA patients 
- 
reduce OA synovitis and/or effusion, determined by musculoskeletal ultrasound (MSK-US); we will 
also use MSK-US to correlate the presence of crystals observed on cartilage both with biomarker 
inflammation and OA response to colchicine 


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To accomplish this, we will employ a well-established SKOA cohort, whom we have been following in 
natural history studies since 2005, and for whom we already possess baseline clinical, radiographic, 
ultrasound, genetic, PBL genomic and plasma/serum biomarker data. 
1.5 
Dose Rationale 
 
Subjects will be randomized to take colchicine 0.6mg, 0.8mg, or placebo daily. In gout practice, an option 
to use colchicine 0.6mg (U.S.) or 0.5mg (internationally) once or twice daily is recommended for prophylaxis 
of gout flares. For acute flares, a dosing regimen of 1.2 mg followed by 0.6mg 1 hour later showed no 
greater gastrointestinal adverse events than placebo (Terkeltaub A&R 2010). For our study, a new, once-
daily dose of colchicine 0.8mg is being formulated. This dose was chosen because we expect it to be 1) 
almost universally tolerated, 2) likely to have a higher compliance rate than twice-daily dosing, 3) less likely 
than twice daily dosing to require dose adjustment for co-morbidities or concomitant medications and 4) 
potentially more efficacious than a once-daily 0.6mg dose. However, because recent studies suggest that 
a dose of 0.6mg may be sufficient for chronic inflammatory suppression and may reduce the already low 
risk of toxicity of 0.8mg, for the remainder (second half) of the study we will switch from the 0.8mg to a 
0.6mg dose to allow comparison of the two doses (36).  
1.6 
Research Risks & Benefits 
1.6.1 
 Risks of Study Drug 
As a bioactive substance, colchicine is generally well tolerated within the dose range being studied. 
However, some patients may experience upset stomach, nausea/vomiting and/or loose stools. Colchicine 
can induce bone marrow suppression and a neuromyopathy, mostly after overdose; such occurrences 
would be extremely rare at the doses and duration being studied, particularly since we will exclude 
individuals whose metabolism of colchicine may be altered by liver disease or medication use. See 
Appendices I (PI – Package Insert) and II (MSDS-Material Data Safety Sheets). 
1.6.2 
Other Risks of Study Participation 
 
Blood Drawing  
Risks of venipuncture include bruising, pain at site of phlebotomy, fainting, and rarely, infection. 
 
Ultrasound 
The ultrasound assessment does not pose any adverse risks, dangers or radiation exposure. It is a standard 
procedure performed by trained MDs frequently employed during arthritis care to assess for signs of 
inflammation and structural abnormalities in and around the knee. The ultrasound probe is placed onto the 
skin and mild pressure is applied using a lubricating gel in between to improve the image quality on the 
screen. The pressure might be uncomfortable, but it should not cause any bruising, bleeding, or injury. 
 
For evaluating the knees by ultrasound, there is no gold standard method in the literature.  
Thus we will capture 5 semiquantitative scores on a scale of 0-3 (see below) for osteoarthritis, and 3 yes/no 
questions about crystal disease.  
 
1)    Size of effusion in the anterior suprapatellar space in the longitudinal view, anechoic and 
compressible, on a scale of 0-3 (by millimeter cutoffs) 
2)    Degree of synovial hypertrophy (by gray scale) in the anterior suprapatellar space in the 
longitudinal view, hypoechoic and NOT compressible, on a scale of 0-3 
3)    Degree of synovitis by Doppler signal in the anterior suprapatellar space in the longitudinal 
view,  on a scale of 0-3 (none, scattered, less than 50%, greater than 50% of the area)  
4)    Size of osteophytes in the medial or lateral joint lines (whichever more severe) in the longitudinal 
view, hyperechoic, on a scale of 0-3  


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5)    Degree of femoral articular cartilage (FAC) wear in the suprapatellar transverse view with knee 
flexed, on a scale of 0-3 
6)    FAC double contour sign (hyperechoic line across top of anechoic FAC) in the suprapatellar 
transverse view with knee flexed:  yes/no 
7)    FAC evidence of CPPD (hyperechoic deposits in the middle of the anechoic FAC) in the 
suprapatellar transverse view with knee flexed: yes/no 
8)    meniscal evidence of CPPD (hyperechoic deposits in the triangular meniscus edges) in the 
medial and/or latera joint line:   yes/no 
Knee Radiographs  
As an entry criterion, bilateral standardized knee radiographs showing the presence of a Kellgren-Lawrence 
grade 2 or 3 osteoarthritis in at least one knee within the past year will be required.  The knee radiograph 
will need to be in the NYU Langone system. Any patient who is being considered for entry into the study 
and has not had X-rays within the past year will be expected to undergo standardized X-ray studies for 
confirmation during the screening visit. The X-ray will need to be read by the study radiologist. If the patient 
already has an existing knee radiograph that was conducted at NYU Langone, then this X-ray will need to 
be read by the study radiologist.  There is minimum radiation exposure associated with this procedure. 
 
Knee Arthrocentesis for Synovial Fluid Sample  
Arthrocentesis involves the use of a needle to remove a quantity of fluid from the joint, in this case the knee, 
if swollen. It is a standard procedure performed by trained MDs frequently employed during arthritis care to 
assess inflammation, reduce pain and improve function. The most likely risks are temporary local pain 
during the procedure, and occasional bruising. To mitigate pain to the greatest extent possible we will 
employ local anesthesia (anesthetic topical spray followed by a soft-tissue lidocaine injection), and perform 
the procedure under ultrasound guidance, which typically shortens the procedure time. Patients with larger 
effusions may derive pain relief from the volume decompression of the procedure. The most concerning 
risk of arthrocentesis is the potential for introducing an infection from the skin into the joint. In general 
practice this risk appears to be extremely low based on available data, between 1 in 1,000 and 1 in 10,000 
procedures. We will minimize this risk by 1) using meticulous aseptic technique; 2) only attempting to 
aspirate synovial fluid from patients with ultrasound confirmation of an effusion; 3) using ultrasound 
guidance for the procedure to reduce the need for blind exploration with the needle to reach the effusion 
pocket. Knee Arthrocentesis will be performed at the screening visit and three month visit for the subset 
that qualifies and consents to this additional study procedure. This procedure may be performed in one or 
both knees depending on ultrasound findings.  
 
Bilateral Physical Knee Exam 
This assessment does not pose any adverse risks or dangers. It is a standard exam performed by trained 
MDs frequently employed during arthritis care to assess inflammation, pain, tenderness, and function. It will 
be performed by a study physician. Participants will be asked to stand during this assessment and to bend 
their knees. This study procedure will be performed at the screening visit and the three month visit.  
 
Risk to Privacy and Confidentiality 
As with all research studies, the risk of participating in this study involves a loss of privacy and 
confidentiality. However, the study team and study doctors will assign each subject with a four-digit 
screening number in sequential order of the screening visit date. All participants who are eligible for this 
study after the screening visit will be assigned a five digit subject ID number at baseline in sequential order 
of the baseline visit date. These numbers will be put on the subject’s questionnaires and samples so their 
names and identifying information will not be disclosed. Only the PI, Dr. Michael Pillinger, and his study 
team will have the information that links the name and study number. They will keep that information in a 
secured location accessible only to select research staff.   All digital data collected in the study will be 
maintained in a secure REDCap file, which is password–protected. 
 


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1.6.3 
Potential benefits 
 
Subjects participating in this research may potentially benefit from improved pain, function and quality of 
life as a result of the study medication. However, it is unknown whether or not the study drug will help 
subjects with osteoarthritis. Indirectly, information from subjects in this study may eventually help other 
avoid the consequences of OA and its co-morbidities in the future. 
 
2 
Study Objectives 
 
Purpose: OA is a common, painful, and debilitating form of arthritis for which no disease modifying therapy 
currently exists. Studies from our group and others indicate that OA is accompanied by occult inflammation, 
suggesting that inflammation may contribute to disease symptoms/progression. Colchicine is an anti-
inflammatory agent used commonly for gout. Colchicine mechanisms of action target several processes 
implicated in OA, and small preliminary studies suggest that colchicine may ameliorate OA knee pain. We 
therefore propose a double-blind, randomized, placebo-controlled trial to test whether colchicine treatment 
of symptomatic knee OA (SKOA) patients will lower pain scores and improve physical function. We 
hypothesize that clinical improvement will be associated with reduction of inflammatory candidate genomic, 
plasma and synovial fluid biomarkers, and with improved imaging outcomes. We will recruit subjects from 
a well-established SKOA cohort, Leukocyte Gene Expression in Osteoarthritis (LGEO), whom we followed 
in a prospective natural history study beginning in 2005 (NIH R01 AR052873, PI Abramson), and who have  
completed that observational study. To the fullest extent possible, our interventional study will employ as 
entry criteria assessments and outcome measures used in the parent observational study, including clinical, 
radiographic, ultrasound, peripheral blood genomic, and plasma/serum biomarker results for these 
subjects. 
 
Objective 1: To test whether daily colchicine treatment for three months improves clinical outcomes 
in SKOA. Patients will be assessed for clinical outcomes (i.e., pain, physical function) using VAS (Visual 
Analog Scale) for pain and KOOS (Knee Injury and Osteoarthritis Outcome Score) instruments. Pain 
medication use will be evaluated at each assessment time.  
 
The primary clinical outcome will be the difference in mean changes of VAS pain scores between 
treatment groups at 3 months. The VAS scale asks patients to rate the pain that they’ve had in each 
knee during the past 30 days on a scale of 0-10, where "0" means "No pain" and "10" means "Pain as 
bad as you can imagine."  
 
Secondary clinical outcomes will include: 
• 
mean changes and absolute differences in the Knee Injury and Osteoarthritis Outcome 
Score (KOOS) for pain between and within the groups at 3 months.   
• 
mean changes and absolute differences of KOOS stiffness, physical function and total 
KOOS scores between and within the groups at 3 months. 
• 
mean absolute doses and changes in dosage of acetaminophen or other medications 
used for pain between and within the groups at baseline and 3 months. 
 
Objective 2: To test whether colchicine suppresses peripheral blood leukocyte (PBL), plasma and 
synovial fluid OA biomarkers of inflammation (Abramson Lab).   
 
PBL Genomic Studies. PBL will be isolated from all subjects at baseline (or end of parent study if within 3 
months) and 3 months. qPCR will be performed on PBL RNA (buffy coat PBMC).The qPCR panel will be 
based on our preliminary findings, likely including IL-1β, TNF-α, IL-1Ra and COX-2. qPCR data will be pre-
processed for quality control, including correction of off-scale measurement and normalization. To obtain 
comparable results across assays, we will use the comparative CT method (2-ΔΔCt method) as our 
normalization strategy. Logarithmic transformation will be performed on gene expression data if not 
normally distributed. We will use the qPCR library (http://www.dr-spiess.de/qpcR.html) within Bioconductor 
2.6. 


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Plasma protein/lipid biomarker specimens will be collected from all subjects at baseline and 3 months, 
including IL-1Ra, PGE2, 15-HETE, highly sensitive C-reactive protein (hsCRP), MMP-1, MMP-3, MMP-9 
and urate. MMP-1, 3 and 9 levels will be assayed via multiplex ELISA (#K15034C-1), and hsCRP using 
#K151STD-1, (Meso Scale Diagnostics). IL-1Ra will be evaluated using #DRA00B from R & D systems. 
PGE2 and 15-HETE will be analyzed using the ACE competitive EIA kit (Cat no:514010; Cayman Chemical, 
MI). IL-1β and TNF-α soluble protein levels will not be assessed, as we have previously shown that these 
levels do not accurately reflect knee OA severity owing to low levels and measurement limitations. 
 
Synovial Fluid (SF) Studies (Optional). Subjects will undergo arthrocentesis during their screening and 
three month visits if effusion is detected on ultrasound and they consent to participate in these substudies. 
Thus, we expect to collect SF from a potentially more “inflammatory” subset of SKOA subjects. SF markers, 
measured by ELISA in the laboratory of our collaborator Dr. Mukundan Attur, will include IL-1β, TNF-α, IL-
1Ra, IL-18, MMP-3, MCP-1 and urate. The SF studies are optional and will be exploratory to comprise only 
part of a sub-aim of the study.   
Only coded samples will be sent to Dr. Attur.  He will not have access to the key which links the subject 
identity to the subject code for the sample. Dr. Attur’s Immunology laboratory will do the synovial fluid, 
blood, and plasma studies.    
 
Objective 2a: We will compare absolute levels and mean changes in PBL gene expression levels for 
IL-1β, TNF-α, IL-1Ra, and COX-2 between baseline and 3 months in colchicine and placebo groups; we 
will also examine whether levels of individual biomarkers significantly change between baseline and 3 
months within each group. 
 
Objective 2b: We will compare absolute levels and mean changes in plasma levels of IL-1Ra, PGE2, 
15-HETE, MMP-1, MMP-3, MMP-9 and CRP between baseline and 3 months in colchicine and placebo 
groups; we will also examine whether levels of individual biomarkers significantly change between baseline 
and 3 months within each group. 
 
Objective 2c: We will compare absolute levels and mean changes in SF IL-1β, TNF-α, IL-1Ra, IL-18, 
MCP-1, MMP-3, and urate between baseline and 3 months, in colchicine and placebo groups; we will also 
examine whether levels of individual biomarkers significantly change between baseline and 3 months within 
each group. We will additionally examine associations of SF biomarkers with their peripheral blood 
correlates (e.g. SF IL-1β with PBL IL-1β gene expression) at each time point measured 
 
Aim 3: To determine the impact of three months of daily colchicine on musculoskeletal ultrasound 
(MSK-US) signs of synovitis and effusion:  
 
MSK-US: We will assess for urate (as double-contour sign) and calcium pyrophosphate crystal (CPP; as 
chondrocalcinosis) deposition as well as degenerative change in the articular cartilage, CPPD in the 
menisci, effusions, osteophytes and synovitis, using standardized ultrasound methodology as well as 
specific approaches for synovitis. Jonathan Samuels, MD, or team physicians trained by Dr. Samuels, will 
scan the longitudinal suprapatellar, flexed transverse suprapatellar, medial and lateral views of the knee, 
using a frequency of 18 MHz (MyLab25 Gold, Biosound Esaote, Indianapolis Indiana). Subjects will undergo 
arthrocentesis during their screening and three month visits if effusion is detected on ultrasound and they 
consent to participate in these substudies. 
 
Objective 3a. We will compare changes in synovitis and effusion between colchicine and placebo 
groups. Mean changes in MSK-US-measured synovitis and effusion at 3 months will be compared between 
the two groups, as well as within each group. We hypothesize that, consistent with our prior observations, 
OA patients will frequently demonstrate synovitis; and that synovitis will improve after colchicine but not 
placebo treatment.  
 
Objective 3b. We will compare rates of crystal deposition (urate, calcium) on MSK-US between 
colchicine and placebo groups over three months, and assess the relationship between crystal 
deposition, OA severity, levels of inflammation and response to colchicine. We will examine the 


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association of crystal deposition and OA severity by KL grade and OARSI atlas measures. We will also 
examine whether crystal deposition associates with PBL, plasma, and especially SF inflammatory 
mediators. We hypothesize that some OA patients will have previously unappreciated crystal deposition, 
that may correlate with indices of pain and inflammation. We will determine whether colchicine treatment 
alters any associations found 
3 
Study Design 
3.1 
General Design 
This Phase 2, prospective, double-blind, placebo-controlled, randomized trial will enroll 120 SKOA subjects 
through the Peter D. Seligman Center for Advanced Therapeutics which is located the at the NYU Langone 
Orthopedic Center (333 East 38th Street, Fourth Floor), New York, New York 10016.  Patients meeting entry 
criteria will be randomized 1:1 to treatment with colchicine or placebo daily for three months. Subjects will 
have detailed evaluation of standardized clinical pain outcomes, candidate peripheral blood biomarkers, 
baseline knee radiographs as well as MSK-US, and a subset will undergo evaluation of their synovial fluid.  
 
 
 
 
 
3.2 
Primary Study Endpoints 
 
Outcomes Measured: Clinical assessments for symptoms and medication use will be made for each study 
visit (according to Table of Study Visits/Procedures. Biomarker blood samples will be obtained at baseline 
and 3 months. MSK-US and synovial fluid will be measured on a subset of the cohort (described below) at 
screening and 3 months.  
 
The primary outcome will be the difference in mean changes of VAS knee pain scores (as average daily 
pain) between colchicine treatment (both doses) and placebo groups at 3 months.   
3.3 
Secondary Study Endpoints 
 
Secondary outcomes will include: 
• 
Mean changes and absolute differences of KOOS pain scores between and within the 
groups at 3 months. 
• 
Mean changes and absolute differences of KOOS stiffness, physical function and total 
KOOS scores between and within the groups at three months. We will also collect 
pain/stiffness data in a subject diary [Appendix I] on a daily basis. 


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• 
Mean absolute doses and changes in dosage of acetaminophen or other medications 
used for pain between and within the groups at baseline and three months (using a 
subject diary). 
• 
Mean changes and absolute differences of peripheral blood leukocyte (e.g. IL-1β, TNF-
α, IL-1Ra and COX-2), plasma (e.g. IL-1Ra, PGE2, 15-HETE, highly sensitive C-
reactive protein (hsCRP), MMP-1, MMP-3, MMP-9 and uric acid) and synovial fluid 
(e.g.IL-1β, TNF-α, IL-1Ra, IL-18, MCP-1, MMP-3, and urate) OA biomarkers of 
inflammation  between and within the groups at 3 months. 
• 
Mean changes in MSK-US-measured synovitis and effusion at 3 months will be 
compared between the two groups, as well as within each group. 
• 
Assessment of rates of crystal deposition (urate, calcium) on MSK-US between 
colchicine and placebo groups over 3 months, and assessment of the relationship 
between crystal deposition, OA severity, levels of inflammation and response to 
colchicine. 
• 
Differences in all the above outcomes between colchicine users in the 0.8mg vs 0.6mg 
groups. 
3.4 
Primary Safety Endpoints 
 
Primary safety endpoints will include assessment, as clinically indicated, for the most common adverse 
reactions known to occur with colchicine, including the following symptoms and signs: 
Abdominal cramping, abdominal pain, diarrhea, nausea, vomiting 
 
Although not expected, we will also assess for secondary safety endpoints, including: 
• 
Neurological: weakness or numbness 
• 
Dermatological: hair loss or rash 
• 
Musculoskeletal: muscle weakness or pain  
4 
Subject Selection and Withdrawal 
4.1 
Inclusion Criteria 
 
1. Capable of giving informed consent in English. 
2. 40 years of age or older. 
3. Have a clinical diagnosis of knee OA as per ACR criteria. 
4. Have frequent knee symptoms defined as pain, aching, or stiffness in or around one or both 
knees on most days (i.e. more than half) for at least one month in the past 12 months.  
5. VAS pain greater than or equal to 30mm in at least one knee in the month prior to the 
screening visit.   
6. Have KL grade of 2 or 3 demonstrated on knee radiograph, in at least one painful knee.  
7. Have an estimated glomerular filtration rate (eGFR) > 30 ml/min (MDRD equation) and liver 
transaminases < 2x the upper limit of normal. 
8. Have a BMI ≤ 35kg/m2 at the time of enrollment. 
9. Agree to refrain from taking oral or topical non-steroidal anti-inflammatory medications 
(NSAIDs) and intra-articular therapies to the knees for the duration of the study. Low doses of 
aspirin (≤325mg) that do not act in an NSAID capacity, such as aspirin taken for 
cardiovascular conditions, are acceptable to continue taking during the study. 
10. Agree to refrain from starting any new pain medications (with the exception of 
acetaminophen), including supplements, acupuncture, physical therapy or other non-
pharmacologic modalities for the duration of the study. 


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11. Agree to refrain from changing the dose or frequency of any pain medication regimen (with 
the exception of acetaminophen), acupuncture, physical therapy or other nonpharmacologic 
modalities you are currently taking or participating in for the duration of the study. 
12. Be able to take colchicine or placebo daily for three months. 
13. Females of childbearing potential must use effective contraceptive protection (e.g., birth 
control pills, intrauterine device, barrier method) during the treatment period and 30 days 
after the last dose of study drug. 
14. Male study participants who have female partners of child-bearing potential are required to be 
on effective contraceptive protection (e.g., birth control pills, intrauterine device, barrier 
method) with their female partners during treatment period and for 90 days after the last dose 
of the study drug. 
4.2 
Exclusion Criteria  
 
1. Have received intra-articular therapies (hyaluronic acid,corticosteroid steroid injection, Platelet Rich 
Plasma, stem cell injections, etc.) within the past three months prior to the screening visit.  
2. Have a known diagnosis of gout/pseudogout (acute calcium pyrophosphate arthropathy) or other 
inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy 
etc). Patients with radiographic chondrocalcinosis without clinical pseudogout will not be excluded; 
based on our knowledge of this cohort’s radiographic and MSK-US findings, we anticipate 
chondrocalcinosis prevalence of <10%. 
3. Have any clinical disorder that required the use of corticosteroids within one week of screening visit 
4. Have an estimated glomerular filtration rate (eGFR) < 30 ml/min (MDRD equation) and liver 
transaminases > 2x the upper limit of normal on most recent measurement 
5. Have a BMI > 35kg/m2 at the time of enrollment 
6. Have KL score of 0, 1, or 4.  
7. Have a diagnosis of diabetes mellitus, chronic infectious disease, congestive heart failure, non-
cutaneous cancer within the past 5 years or any other comorbidity that in the investigator’s opinion 
would disqualify the subject 
8. Scheduled or undergoing total knee replacement or other major surgery during the study period 
9. Currently pregnant or plan to become pregnant during the study period 
10. Unwilling to refrain from any medication or herbal supplements that is a strong CYP3A4 inhibitor 
whose metabolism may interact with colchicine (e.g., certain protease inhibitors, certain azole 
antifungal agents, clarithromycin) within 14 days or 5 half-lives, whichever is longer, of the first 
administration of the study intervention in this study. See Appendix II. 
11. Unwilling to refrain from any medication or herbal supplements that when taken with colchicine can 
lead to high levels of colchicine in the body (e.g. some antifungal drugs, HIV drugs, antibiotics, and 
antidepressants) within 14 days or 5 half-lives, whichever is longer, of the first administration of the 
study intervention in this study  
12. Unwilling to refrain from consuming grapefruit or grapefruit juice (CYP3A4 inhibitor) during the study 
period.  
13. Unwilling to refrain from the use of more than 1 glass daily of red wine, or from consumption of 
Seville oranges, pomelos, exotic citrus fruits, or grapefruit hybrids from 7 days before the start of 
the study intervention 
14. Unwilling to refrain from taking oral or topical NSAIDs during the study period. Low doses of aspirin 
(≤325mg) that do not act in an NSAID capacity, such as aspirin taken for cardiovascular conditions, 
are acceptable to continue taking during the study. 
15. Unwilling to refrain from receiving intra-articular therapies to the knees during the study period.  
16. Unwilling to refrain from starting new pain medications (with the exception, including 
supplements, or acupuncture, physical therapy or other pain modalities for the duration of the 
study 
17. Unwilling to be randomized to take colchicine or placebo daily for 3 months 
18. Subjects participating in other clinical studies or taking other investigational drugs  


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19. Nursing mothers 
4.3 
Subject Recruitment and Screening 
 
Subjects will be primarily recruited from the LGEO (Leukocyte Gene Expression and Genetic Biomarkers 
of OA Incidence and Progression: s12-03682) natural history study described in detail below. Subjects will 
initially be recruited from the pool of patients whose most recent knee radiograph (LGEO exit x-ray) 
indicates KL grade 2 or 3. The LGEO study was a previous observational OA study. Previous sample 
collected included blood, synovial fluid, ultrasound, x-ray, and/or MRI. These subjects consented to be 
contacted for future research studies. The investigators also reserve the option to offer participation to 
subjects who have already participated in other prior knee OA studies at the NYU Langone Orthopedic 
Center. If necessary, the investigators may also seek appropriate subjects in their own clinics and practices, 
and will communicate through word of mouth to colleagues in the NYU/NYC rheumatology community. 
Alerts in the form of letters or e-mails to colleague practitioners may be employed, as necessary. The 
investigators may also post the flyer and colleague letter to their personal social media pages (Facebook 
and Twitter) to alert outside physicians and potential candidates about the study. The social media 
interaction will be limited to 1-way communication and people who are interested will be asked to call the 
number listed in the post and not respond via social media. Personal social networking sites cannot be 
used for communication with the study team as privacy cannot be ensured, because we are instructing 
those on social media not to respond on the social media platform but to call the coordinator, privacy will 
be maintained in the same manner as all other recruitment methods. In addition, it may become necessary 
to use DataCore as part of our recruitment plan. DataCore can provide a list of potential subjects, based 
on selected criteria, from various EMR sources, such as EPIC. Our research team will review that list to 
identify potential candidates. Once identified, potential subjects may be contacted, after a chart review. For 
patients who have not previously signed a release to be contacted for research purposes, we will first reach 
out to their primary provider and ask them to obtain patient permission to be contacted. In addition to 
DataCore, i2b2, Slicer Dicer, and MyChart will also be utilized to recruit subjects for the study. Moreover, 
the iConnect Volunteer Registry may be utilized to recruit potential subjects. The registry is available for 
whomever is interested in participating in clinical studies at NYU Langone Health. Volunteers who agree to 
be apart of the registry will be asked to provide standard information, including demographics (age, race, 
gender, etc) and medical history. Our research team may use the registry to identify a list of potential 
volunteers by filtering out medical conditions for knee osteoarthritis. Once identified, potential volunteers 
may be contacted to discuss the study, inquire interest, and complete a phone screen. Alternatively, the 
research team may receive referrals for potential volunteers interested in the study and request to be 
contacted. If potential volunteers fit the baseline criteria to be screened, the research team will obtain 
consent prior to initiating any study procedures. 
 
Finally, we may consider recruitment through our arthritis clinics and primary care clinics at our affiliated 
hospitals, Bellevue Hospitals Center, the VA New York Harbor Healthcare System, and The Hospital for 
Joint Diseases.  Should those sites be used, we will first secure local IRB approval.  
 
Flyers will be distributed electronically or in print versions to rheumatologists, orthopedists and other 
musculoskeletal practitioners at the NYU Langone Orthopedic Center, and to primary care physicians within 
the NYU faculty practice network.  Flyers will be displayed by the above practitioners in their offices at their 
own discretion. 
 
Screening and Consent: SKOA (s14-00290) cohort subjects who meet entry criteria will be invited to 
participate in our prospective, double-blind, placebo-controlled, randomized trial. Subjects will be 
approached for written informed consent in accordance with the policies of the NYU School of Medicine 
Institutional Review Board and GCP and ICH Guidelines.   
 
Subjects may also be screened over the phone using the Telephone Screening Interview form.  
 
Signal Knee Selection 


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Signal knee is the knee that will be assessed for the duration of the study. For the purposes of identifying 
the signal knee, pain proceeds KL severity.  If pain and KL severity are equal in both knees, then it will be 
up to the discretion of the physician as to which knee to follow for the purpose of the study.   
 
 
a. Number of Subjects  
Approximately 120 knee OA subjects will be enrolled in all arms of the study.  
b. Gender of Subjects  
Subjects will not be restricted by gender, although we anticipate that a majority of subjects will be female 
as the disease is more common in women, and the parent study pool is 63% female.  
 
 
c. Age of Subjects 
Subjects will be 40 years or older by the start of the study period. 
 
d. Racial and Ethnic Origin 
Subjects will not be selected or restricted according to racial or ethnic origin. Rather, the breakdown of 
these demographics in our study is expected to reflect the population of the parent pool the patients are 
being recruited from.  
 
e. Vulnerable Subjects  
Certain vulnerable subject groups, as specified by Federal regulations (e.g., pregnant women, neonates, 
children, and terminally ill patients) will either be ineligible to participate or will be specifically excluded (or 
will have already been excluded from the LGEO study). OA is a disease seen predominantly in aging; thus 
pregnant women would not likely be diagnosed with OA.  Moreover, although colchicine use in clinical 
practice is often continued in pregnant women with familial Mediterranean fever, we will exclude all pregnant 
women from this study as a risk-benefit consideration. Neonates and children are under age 40, making 
them ineligible for the study. Terminally ill patients will be excluded, as they may not be able to complete 
the duration of the study based on life expectation and/or functional status. Subjects who lack capacity to 
consent for themselves, e.g. cognitively impaired persons, will be excluded. Members of minorities, 
economically and/or educationally disadvantaged persons, and students and employees will be eligible to 
participate if they meet inclusion and exclusion criteria. However, we will consent only in English for this 
study. 
 
It is possible that employees of NYU Langone Health System may express interest in participating in the 
study, creating the need to define employees as a potential vulnerable population due to their employability 
at the institution.  No employees will be coerced into participating, nor will their disinterest in participating 
be held against them in any way. In sum, their employability will not be impacted based on whether or not 
they choose to participate in this study and it will be fully explained to them that their potential involvement 
in the study will not impact their job position, future job standing, or employee evaluation. 
 
Further it is possible that students of NYU may wish to participate in this study. No students will be coerced 
into participating, nor will their disinterest in participating be held against them in any way.  It will be fully 
explained to them that their decision to participate, or not to participate, in this study will not influence or 
impact their status, position, standing, or grades at NYU. No study personnel are involved in the grading 
and evaluation of the students that are to be potentially recruited. Should employees or students choose to 
participate; the study team will treat their privacy and confidentiality with the highest regard and make every 
effort to ensure that the knowledge of their involvement is limited to the study staff and the participating 
individual. 
 
4.4 
Early Withdrawal  
Subjects may voluntarily withdraw from study participation at any time without having to provide a reason. 
Alternatively, subjects may be withdrawn at the investigator’s discretion if it is in the subject’s best 
interest. Subjects who become pregnant during the study will be withdrawn from the study. 
 


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Every effort will be made for withdrawn subjects to undergo end of study assessments, regardless of the 
reason for withdrawal. If a subject refuses end of study procedures, the reason for refusal will be fully 
documented in the subject’s source document and recorded in the study specific eCRF in REDCap. It is 
the subject’s right to withdraw from the trial without providing a reason. In this case, the source documents 
and the eCRF should document the reason for discontinuation as “withdrawal of consent”. Withdrawn 
subjects will not be replaced.  
 
Whilst the effect of withdrawals will be investigated, subjects withdrawing for any reason will be counted as 
non-remitters in the primary analysis and therefore no adjustment in sample size for withdrawals is 
necessary.  
 
Discontinuation of Study Therapy  
 
Subjects may discontinue taking study medication at any time. In the event subjects permanently 
discontinue study medication, they will be asked to return for remaining study visits. All subjects, whether 
completing the study or withdrawn prematurely, will be followed up through the last visit on the schedule of 
assessment.  The study team will collect any new adverse events (AEs) and concomitant medications at 
every visit. 
 
If any subject is discontinued from study therapy, an explanation of this clinical decision will be 
documented. If the reason for discontinuing study therapy is an AE or an abnormal laboratory test result, 
the specific event or test will be recorded in the eCRF. Subjects who are discontinued from study therapy 
will undergo all study assessments up to and including the early termination visit, if possible. 
 
Discontinuation of Study Drug Due to an AE or SAE 
 
Subjects may be permanently discontinued from study drug because of an AE or SAE. It is vital to obtain 
follow-up data on any subject withdrawn because of an AE or SAE. In any case, every effort will be made 
to evaluate protocol-specified safety follow-up procedures (i.e., Reporting Procedure for AEs, SAEs and 
Pregnancy). If a subject is withdrawn due to an AE or SAE, the event will be followed by the Investigator 
through contact with the subject until resolution or stabilization has occurred. All AEs should be followed 
until resolution, stabilization or the subject is lost to follow-up and cannot be contacted. 
 
4.4.1 
When and How to Withdraw Subjects 
 
Participants will be informed that they are free to withdraw from the study at any time. Subjects will otherwise 
be withdrawn if they experience serious adverse events to the study intervention, or non-serious adverse 
events that fail to resolve with ongoing treatment and/or temporary dose withholding. 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects 
 
If patients choose to withdraw from the study, as delineated in the consent form, they can write a letter to 
the study team formalizing this request. We will include in the consent language that states that if a patient 
withdraws, the study will maintain her/his data as well as samples up to the point of withdrawal, for intention-
to-treat analysis.  Subjects who wish to withdraw their information and/or biosamples from the study will be 
required to submit an explicit written request, and their request for withdrawal will be kept on file by the 
study team as part of documentation for the study records. Every attempt will be made to contact the patient 
at what would otherwise be the end of the treatment period to collect data on the primary outcome, including 
phone calls to the subject weekly. 
 


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5 
Study Drug  
5.1 
Description 
 
The study drug (colchicine) will be 0.6 mg or 0.8 mg capsules.  An identical placebo capsule will be 
provided. The study drug and placebo capsules will be provided by Hikma Pharmaceuticals, which is FDA 
approved to produce colchicine at a dose of 0.6 mg. The IND has been submitted for the 0.8 mg dose 
and will also include the 0.6 mg dose.  
5.2 
Treatment Regimen 
Subjects will be randomized to take oral colchicine (0.6mg or 0.8mg), or oral identical placebo once daily 
(in the morning) for 90 days. Subjects will be instructed to take the study drug in the morning around the 
same time daily. 
 
5.3 
Method for Assigning Subjects to Treatment Groups 
 
A randomization code will be generated by the statistician using random block sizes and held by the 
research pharmacist.   
 
5.4 
Preparation, Storage and Administration of Study Drug 
 
 
Hikma Pharmaceuticals will provide matching study drug and placebo capsules. The study medication will 
be maintained and stored by the NYU Langone Orthopedic Center Pharmacy located at 333 East 38th 
Street, Fourth Floor, New York, New York 10016.  
 
The study medication will be maintained and dispensed by the Pharmacy after randomization at the 
baseline visit.  
The study medication will be dispensed as 90 tablets.  
 
At both the Pharmacy, and at home by the subjects, study medication will be stored at a temperature 
between 20° and 25° C (66°-77° F), and protected from light and moisture. Instructions for storage will be 
labeled both on the shipments from Hikma, and on the bottles individually dispensed to the subjects. 
5.5 
Subject Compliance Monitoring 
 
Subject Diary:  
 
Each subject will be given a subject diary for the duration of the study. The subject diary will include data 
on medication compliance, pain (10-point Likert scale), other pain medication use, potential side effects 
and opportunity for additional comments. Subjects will be asked complete a daily entry and will be asked 
to do so around the same time every night for the duration of the study. See Subject Diary in Appendix I 
 
Questionnaires: 
 
Medication use will be reviewed and recorded at each visit to confirm medication adherence. Study drug 
pill counts will be performed at each study visit to assess study compliance. See Medication Compliance 
Form in Appendix III.  
 
5.6 
Prior and Concomitant Therapy 
 


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At screening, baseline, and all follow up visits, all concomitant medications will be recorded. Patients will 
be allowed to take acetaminophen (as first line therapy), topical analgesics (except topical diclofenac) and 
other pain medications at FDA-approved doses that they were using prior to the study, except NSAIDs. 
Subjects will record any analgesic use in their subject diaries. Initiation of new analgesic medications or 
changes to pain medication regimen will not be allowed for the duration of the study. Intra-articular therapies 
(hyaluronic acid,corticosteroid steroid injection, Platelet Rich Plasma, or any stem cell injections will not be 
allowed during or within 3 months prior to the start of the study.  
 
5.7 General Method of Preparation and packaging 
– 
General description of how drug is manufactured/prepared 
Blending:  
The Colchicine, USP and Microcrystalline Cellulose, NF (Avicel pH 101) are passed through an 8 
mesh screen and then charged into two #4 Ball Mill Jars with approximately 9kg of grinding media 
per jar.  The jars are sealed and then rolled for eight hours.  The material is discharged through a 
screen to remove the grinding media from the mixed material. 
 
Concurrent with the ball milling, the Anhydrous Lactose, NF is processed in a fitzmill with Hammers 
Forward at High Speed using a #0 screen (1532-0027). 
 
The Colchicine/Avicel mix, Milled Lactose, Sodium Starch Glycolate, NF, and Colloidal Silicon 
Dioxide, NF are passed through a 20 mesh screen, loaded in a 7 ½ cubic foot tumbler, and mixed 
for 22.5 minutes. 
 
The Magnesium Stearate, NF is passed through a 30 mesh screen and then charged to the 
tumbler in 5 equal parts, each of which is followed by a one minute mixing time.  
 
After the blended material is sampled, it is discharged into drums as Colchicine – Final Blend, and 
held until in-process testing is complete and the material is ready for encapsulation.  
 
Encapsulation: 
A GKF 1500 Capsule Filler with a 7.5mm Dosing Disc and a CP-350 Capsule Polisher are used 
for the encapsulation process.  A KKE 1500 is used to check weigh the filled capsules and a 
MET30+ metal detector inspects the capsules prior to depositing them into a bulk capsule 
container. 
 
The Colchicine – Final Blend is loaded into the powder hopper of the GKF 1500 Capsule Filler.  
No.4 med Orange/Lt Blue Opaque Hard Gelatin Empty Capsules are loaded into the empty 
capsule hopper of the GKF 1500.  The capsule filling machine is adjusted to achieve the desired 
target fill weight, including adjustment of the tamping settings on the filler.  
 
– 
Acceptable limits and analytical methods used to assure the identity, strength, quality, and purity 
of the drug substance: 
 
Physical & Chemical Test 
Requirements 
Specification 
Methodology 
Description 
Pale yellow to pale greenish 
yellow crystalline powder 
Visual 
(SOP-196) 
Identification (IR) 
Exhibits comparable maxima at 
same wavelengths as standard 
USP <197K> 
Specific Rotation 
-240° to -250° 
USP <781S> 


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Water 
NMT 2.0% 
USP <921> Method I 
EP F Colchicine 
NMT 0.15% 
HPLC (TM-1775) 
Limit of Ethyl Acetate 
NMT 6.0% 
GC (TM-1855) 
Heavy Metals 
NMT 20 ppm 
USP <231> Method 
II 
Residue on Ignition 
NMT 0.2% 
USP <281> 
Assay (on anhydrous, solvent 
free basis) 
94.0% - 101.0% 
HPLC (TM-1756) 
Residual Solvents: 
• Chloroform 
• Ethanol 
• Methanol 
• Methyl Chloride 
 
NMT 100 ppm 
NMT 5000 ppm 
NMT 3000 ppm 
NMT 600 ppm 
GC (TM-1710) 
Impurities 
• EP D: Colchicoside 
• EP E: 3-O-demethylcolchicine 
• EP B: Conformational Isomer 
• EP A: N-deactyl- 
N-formylcolchicine 
• y-lumicolchicine 
• EP C: β-lumicolchicine 
• Highest Unspecified Impurity 
• Total Specified and 
 Unspecified Impurities 
 
NMT 0.15% 
NMT 0.15% 
NMT 2.0% 
NMT 0.15% 
 
NMT 0.06% 
NMT 0.06% 
NMT 0.10% 
NMT 3.0% 
HPLC (TM-1756) 
Particle Size 
 
D90 
 
D50 
 
D10 
 
NMT 50µ 
NMT 20µ 
NMT 10µ 
HELOS (SOP-585) 
XRD 
Conforms to current USP RS 
USP <941> 
Bulk Density 
0.10 – 0.40 g/mL 
(SOP-107) 
 
– 
Information sufficient to support stability of the drug substance during proposed human testing 
Finished product manufactured with Colchicine drug substance has been placed on accelerated 
and room temperature stability.  Six month data is available for both conditions in bottles of 15’s, 
100’s, and 1000’s.   
– 
NOTE:  Reference to the current edition of the United States Pharmacopoeia – National Formulary 
may satisfy relevant requirements in this section.-THIS IS NOT A USP PRODUCT! 
5.8 Drug Components and Drug Product 
 
– 
Ingredient 
Mg/cap 
Function 
Colchicine, USP 
0.6 mg or 
0.81mg1 
Active 
Microcrystalline Cellulose, NF (Avicel pH 101) 
5.65mg 
Diluent 
Anhydrous Lactose, NF (Tablet Grade) 
101.77mg2 
Diluent 
Sodium Starch Glycolate, NF (Primojel) 
3.4mg 
Disintegrant 
Colloidal Silicon Dioxide, NF (Cab-o-sil) 
0.56mg 
Glidant 
Magnesium Stearate, NF 
1.13mg 
Lubricant 


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#4 Med Orange/Lt. Blue Hard Gelatin Capsules 
printed “Hikma Pharmaceuticals119” in white ink 
(40mg) 
Encapsulation 
Total Weight (Target Filled Capsule) 
153.32mg 
--- 
1Equivalent to 0.808mg/cap (1% excess based on Anhydrous, Solvent Free Basis, adjusted for assay, moisture 
content, and ethyl acetate. 
2Adjusted to make Total 113.32mg/cap 
 
Microcrystalline cellulose (Avicel pH 101) was selected as a diluent and carrier of the colchicine 
drug.  Microcrystalline cellulose has a particle size of 50 microns which is very close to the particle 
size of colchicine.  These two ingredients are Ball Milled together to mill any larger colchicine 
particles and to prepare a triturate of colchicine in order to obtain a proper content uniformity in 
the final product.  Anhydrous lactose, DT grade was selected to obtain a free flowing blend which 
can aid in the weight uniformity during the encapsulation process.  Sodium starch glycolate 
(Primojel) was used for faster dissolution.  Colloidal silicon dioxide (Cab-O-Sil) was used as a 
glidant.  Magnesium stearate, NF Hyqual grade, with a particle size limit of 50th percentile between 
10.5-16.5 microns, was selected as a lubricant.  
 
The following components used in the manufacture of Colcichine Capsules, 0.8mg are 
compendial: Microcrystaline Cellulose, Anhydrous Lactose, Sodium Starch Glycolate, Colloidal 
Silicon Dioxide and Magnesium Stearate. 
 
The only non-compendial component is the empty hard gelatin capsule, which is commonly used 
in the manufacture of pharmaceutical capsule products.  
 
The gelatin capsules are provided by Suheung Co., Ltd, Seoul, Korea.  Capsules are 
manufactured from cow or pig sources and are certified BSE and TSE free. 
 
 
Blend Specifications 
Test 
Test Specifications 
Test Results 
Uniformity of Blend (Content Uniformity) “C” sample 
_ 
X 
%RSD 
 
90.0 – 110.0% 
NMT 5.0% 
 
98.6% 
1.2% 
Bulk Density (g/mL) 
Tentative 
035 – 0.75 g/mL 
0.56 g/mL 
Particle Size (Sieve Analysis) 
 
40 mesh 
100 mesh 
Pan 
Tentative 
NMT 10% 
NMT 45% 
NLT 40% 
 
0% 
8% 
91% 
 
Finished Product Specifications 
Test 
Test Specifications 
Test Results 
Average Capsule Weight: 
Range 
(Target: 153 mg) 
142 mg – 164 mg 
155 mg 
Average Capsule Content: 
Range 
(Target: 113 mg) 
102 mg – 124 mg 
113 mg 
Dissolution: Colchicine 
NLT 80% (Q) in 20 
minutes (Tentative) 
X 
100% 
Min 
97% 
Max 
104% 
Stage 
1 
Uniformity of Dosage: 
 
 


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Content Uniformity 
Acceptance Value (AV) 
X = 
SD 
 
AV NMT 15.0 
Report Result 
Report Result 
 
5.6 
100.1% 
2.35 
Water Content 
NMT 2.0% 
1.0% 
Assay 
90.0% - 110.0% 
99.3% 
Impurities: 
• EP D: Colchicoside 
• EP E: 3-O-demethylcolchicine 
• EP B: Conformational Isomer 
• EP A: N-deacetyl-N- 
formylcolchicine 
• γ -lumicolchicine 
• EP C: β-lumicolchicine 
• Highest Unspecified Impurity 
• Total Specified and Unspecified 
Impurities 
 
NMT 0.15% 
NMT 0.25% 
NMT 2.0% 
NMT 0.25% 
 
NMT 0.6% 
NMT 0.6% 
NMT 0.25% 
NMT 3.0% 
 
0.06% 
ND 
0.5% 
ND 
 
ND 
ND 
< 0.05% 
0.6% 
 
– 
Packaging procedures as appropriate for the product. 
Packaging: 
The Colchicine Capsules, 0.8mg are loaded into the hopper of a slat filler.  Empty HDPE bottles 
are loaded into the bottle unscramble hopper, caps are loaded into the capper hopper, and rayon 
coil is fed into the cottoner (if required).  When the line is started, the empty bottles are oriented 
and blown to clear any residual debris.  The capsules are loaded into the bottle followed by a piece 
of rayon.  The cap is applied and tightened to a torque and then run through an induction sealer 
and retorqued. 
 
5.9 
Blinding of Study Drug 
 
Drug/placebo and a unique subject identifier linked to group assignment will be allocated by the research 
pharmacist, who will not release group assignment to the investigative team until after all subjects have 
completed the protocol and the database has been locked. 
5.10 Receiving, Storage, Dispensing and Return 
5.10.1 Receipt of Drug Supplies 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug receipt 
log filled out and signed by the person accepting the shipment.  It is important that the designated study 
staff counts and verifies that the shipment contains all the items noted in the shipment inventory.  Any 
damaged or unusable study drug in a given shipment (active drug or comparator) will be documented in 
the study files.  The investigator must notify company providing the study drug and placebo of any 
damaged or unusable study treatments that were supplied to the investigator’s site. 
5.10.2 Storage 
 
Colchicine must be stored at a temperature between 20° and 25° C (66°-77° F), and must be protected 
from light and moisture. 
5.10.3 Dispensing of Study Drug 
 


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Colchicine will be supplied to the NYU Langone Orthopedic Center Investigational Pharmacy in bottles of 
1000.  These will contain the appropriate number of pills according to the treatment group to which the 
patient is randomized. Patients will receive detailed dosing instructions during screening and baseline visits. 
Bottles of 90 capsules will be dispensed at the baseline visit.  
5.10.4 Return or Destruction of Study Drug 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and 
drug remaining.  This reconciliation will be logged on the drug reconciliation form [Appendix IV] , signed 
and dated.  Any discrepancies noted will be investigated, resolved, and documented prior to return or 
destruction of unused study drug.  Drug destroyed on site will be documented in the study files.  
6 
Study Procedures 
 
Screening (21-day window to Baseline Visit): 
• 
Patients may be initially screened over the phone;   
• 
Patients will be provided detailed information about the study and will be asked to sign an 
informed consent form prior to undergoing any study-specific procedures; 
• 
Patients will be assessed for inclusion/exclusion criteria, 
• 
Height and weight will be obtained 
• 
Patients will undergo a complete metabolic profile to assess eGFR and liver function, along with a 
complete blood count panel with differential to determine study eligibility. Results from standard of 
care tests within the last 3 months may be used in place of new screening labs to determine 
eligibility, unless the investigator deems it necessary to repeat them. 
• 
Concomitant medications will be reviewed and recorded.   
• 
Medical history will be reviewed and recorded.  
• 
Demographics will also be obtained. 
• 
Patients will complete VAS questionnaires for both knees to help determine the signal knee; 
• 
Standardized bilateral, weight-bearing knee x-ray will be performed if one was not performed in 
the past 12 months at NYU Langone; 
• 
Standardized knee evaluation will be performed bilaterally 
• 
Ultrasound of the knees will be performed bilaterally, using a standardized protocol;  
• 
Synovial fluid sample will be obtained from either knee if the patient has knee effusion detectable 
on musculoskeletal ultrasound and subject to the patient’s agreement to this separate optional 
procedure; 
• 
Serum Pregnancy test will be performed (as appropriate if the patient is female and within 
childbearing age).   
• 
Review and documentation of any adverse events or serious adverse events. 
 
6.1 
Baseline (window) 
• 
Review of inclusion and exclusion criteria for eligibility 
• 
Subject will be randomized if eligible 
• 
Medical history will be reviewed for any changes. 
• 
Concomitant medications will be reviewed for any changes.  
• 
Patients will complete VAS for both knees, KOOS for the signal knee, and pain in other joints 
questionnaires; 
• 
20 mL of blood will be obtained for research laboratory tests; Subject diary, with instructions, will 
be dispensed. Daily diary will include prompts to report the average knee pain over the past 24 
hours, on a 0-10 scale, separately for each knee. 
• 
Study medication will be dispensed. .   
• 
Height and weight will be recorded. 
• 
Review and documentation of any adverse events or serious adverse events. 
 


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6.2 
Visit 1 (Week 6/ Day 42)  
• 
Patients will complete VAS for both knees, KOOS for the signal knee, and pain in other joints 
questionnaires; 
• 
Concomitant medications will be reviewed and recorded. 
• 
Medical history will be reviewed for any changes.  
• 
Medication pill count will be performed.  
• 
Subject diary will be reviewed for compliance.   
• 
Serum Pregnancy test will be performed (as appropriate) 
• 
Height and weight will be recorded.  
• 
Review and documentation of any adverse events or serious adverse events. 
• 
If a patient is unable to return onsite for visit 1, this visit may be completed remotely via 
telephone.  
6.3 
Visit 2 (Week 12/ Day 84) 
• 
Patients will complete VAS for both knees, KOOS for the signal knee, and pain in other joints 
questionnaires; 
• 
Concomitant medications will be reviewed and recorded. 
• 
Patients will undergo a complete metabolic profile to assess eGFR and liver function, along with a 
complete blood count panel with differential. Results from standard of care tests within 3 weeks 
prior to the visit may be used, unless the investigator deems it necessary to repeat them. 
 
• 
Medical history will be reviewed for any changes.  
• 
Medication pill count will be performed  
• 
Standardized knee evaluation, will be performed bilaterally;  
• 
20 mL of blood will be obtained for research laboratory tests. 
• 
 Ultrasound of the knees will be performed, using a standardized protocol;  
• 
Synovial fluid sample will be obtained from either knee if the patient has knee effusion detectable 
on musculoskeletal ultrasound and subject to the patient’s agreement to this separate optional 
procedure; 
• 
Serum Pregnancy test will be performed (as appropriate) 
• 
Height and weight will be recorded. 
• 
Review and documentation of any adverse events or serious adverse events. 
• 
Patients will be informed of all abnormal lab results if they are significantly elevated as compared 
to previous results. 
 
 
6.4 
Visit 3 (Week 16/Day 112) 
• 
Serum Pregnancy test will be performed (as appropriate) 
Procedures/ 
Assessments 
Screening 
Baseline 
Visit 1/Week 
6 / Day 42-1 
Visit 2/Week 
12/ Day 84 1 
 / Early 
Termination 
/ 
Termination 
Visit 
Visit 3/Week 
16/Day 112 1 
28 days post 
dosing visit 


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Windows 
 
(within 21 
days from 
Screening) 
±7 days 
±3 days 
 
Informed 
consent 
X 
 
 
 
 
Inclusion/exclu
sion 
assessment 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Medical 
history and 
review 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
Height and 
Weight 
X 
X 
X 
X 
 
Bilateral 
Physical Knee 
Exam  
X 
 
 
X 
 
Dispensation 
by Pharmacy 
 
X 
 
 
 
Pill Count 
 
 
X 
X 
 
Bilateral VAS 
pain 
Questionnaire  
X 
X 
X 
X 
 
KOOS 
Questionnaire 
for Signal Knee 
 
 
X 
X 
X 
 
Review of 
Subject Diary 
 
X 
X 
X 
 
Pain in other 
joints 
(questionnaire) 
 
X 
 
X 
 
Bilateral Knee 
ultrasonograph
y (see 
Appendix V) 
X 
 
 
X 
 
Bilateral Knee 
x-rays 
 
X 
 
 
 
 
Blood sample 
(complete 
metabolic 
profile - NYU 
Lab)  
X 
 
 
X 
 
Blood sample 
(complete 
blood count 
with diff -NYU 
Lab)  
X 
 
 
X 
 
Serum 
Pregnancy (as 
appropriate) 
X 
 
X 
X 
X 
 
Blood Samples 
 
X 
 
X 
 


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(LOH 
Research 
Lab) 
Synovial fluid 
sample 
X 
 
 
X 
 
Concomitant 
Meds 
X 
X 
X 
X 
 
Adverse 
Events 
X 
X 
X 
X 
 
**Knee x-ray will be performed if subject has not had one within the past 12 months at NYU Langone 
Health. 
1Telephone call prior to every visit will be made to remind subject of appointment date and time, to 
bring in subject diary and study medication (bottle). 
7 
Statistical Plan 
7.1 
Statistical Methods 
  
Descriptive statistics will be used to compare the distributions of baseline subject characteristics. Frequency 
distributions and chi-square tests will be used to screen for major imbalances in the two randomization 
groups for qualitative variables; graphical displays including and box plots and summary statistics (e.g., 
mean, median, standard deviation, ranges, etc.) will be used for quantitative variables with t-tests (after 
appropriate transformations if necessary to meet the assumptions of the methods). For example, we will 
conduct the Kolmogorov-Smirnov or the Shapiro-Wilk test for the continuous outcomes such as VAS, pain 
scores from Aim 1, PBL gene expression, and plasma levels in Aim 2, to confirm normality of measurements 
prior to performing statistical analyses. Detection of outliers will be done using histograms, box-plots, 
normal plots and summary statistics. Where appropriate, logarithmic transformation will be further done.  
 
In order to assess for significant differences in mean changes of continuous outcomes between 
drug/placebo groups, we will perform un-paired T-tests or Wilcoxon nonparametric counterpart where 
deviated from normality. When outcomes are dichotomized (e.g. progressed), we will use the chi-square 
(Fisher exact) test to compare proportions of outcomes between groups. These univariate analyses will be 
followed by multivariate linear (logistic) regression methods for an adjustment of all other potential 
confounding variables. Baseline factors associated with different groups will be also included in a 
multivariable model.  
 
When multiple time points are considered such as at baseline and 3 months, we will model linear trajectories 
of outcome scores across time using mixed-effects (linear) regression models. The models will be specified 
with random intercepts and slopes such that a linear trajectory representing outcome scores will be 
compared between treatment groups. For example, longitudinal changes in all available continuous 
outcome scores over time of follow-ups will be displayed using locally weighted smoothing scatter (lowess) 
plots, identifying nonparametric mean trajectories over time. Mean trajectories will be then modeled with 
mixed-effects linear regression models, and if necessary using segment-linear models to approximate non-
linear mean trajectories for ease of interpretation. Treatment group-specific (as well as a individual-level) 
intercepts and slopes over the period of follow-up will be included as random effects, while other covariates 
will be modeled as fixed effects. All models will be adjusted for other clinical or demographic confounders. 
Residual-based diagnostics will be used to evaluate validity of model assumptions. Two sided p-values 
<0.05 will be considered to be statistically significant. All statistical procedures will be performed using R 
statistical package (www.R-project.org). 
7.2 
Sample Size Determination 
 
The patients will be randomized in a 1:1 ratio to each main arm of the study, for a total of 120 knee OA 
subjects (half colchicine and half placebo).  
 


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Assuming normality, we calculated the statistical power for various detectable effect sizes in a two-sided 
hypothesis test with a significance level of 0.05, where a 1:1 ratio of sample size is assumed between 
cases (treatment) vs. matched controls (placebo). For outcomes that are proportions, we calculated 
power based on rate differences. The table below shows that our sample size will have adequate power 
to detect the listed effect sizes. For example, we will achieve 86% power to detect a standardized mean 
difference of 0.50 between two groups of a size of 60 for each, which corresponds to a relative reduction 
by 50% in continuous outcomes. For dichotomous outcomes such as rates of MSK-US-measured 
synovitis and effusion, N=60 will have sufficient power to detect a difference of rate of 0.27 between two 
treatment groups. Note that for each domain score and the overall score, the power is the same for each 
effect size since they are standardized, but the mean change corresponding to a given effect size differs. 
 
Sample size 
(N)  
Unpaired t-test 
Chi-square test 
Effect size 1 
Power (%) 
Effect size 2 
Power (%) 
20 
0.8 
80 
0.42 
80.6 
30 
0.7 
84.9 
0.36 
80.9 
60 
0.5 
85.9 
0.27 
83 
70 
0.45 
84.2 
0.25 
83 
80 
0.4 
80.9 
0.23 
81.3 
90 
0.4 
84.8 
0.22 
83.4 
1 standardized mean difference of 2 groups  
2 absolute proportion difference of 2 groups 
 
7.3 
Subject Population(s) for Analysis 
 
Because the trial is short, and the anticipated rate of adverse events is low, we anticipate that most of the 
patients initiating the study will complete it.  Our primary analysis will be intention-to-treat, and will include 
all treated patients who received at least one dose of study drug /placebo.  We will also complete 
secondary analyses on only those patients who completed the study protocol to the end of 90 days, and 
exploratory analyses on subjects who were compliant with the study medications.   
8 
Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 


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• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Subjects will be instructed to record the time of occurrence, duration and outcomes of any AEs in their 
subject diary.   
 
Important medical events are those that may not be immediately life threatening but are clearly of major 
clinical significance.   They may jeopardize the subject and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study.  
The sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 


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• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
Enrolled subjects will be asked to sign a medical release form so that the investigative site can easily 
retrieve any medical records resulting from a hospitalization or other medical encounter related to this 
study. 
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator or designee must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events should be 
recorded immediately in the source document, and also in the appropriate adverse event module of the 
case report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results 
should recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats 
and requirements of the various entities to which they are responsible, but at a minimum those events 
that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 
For Narrative Reports of Safety Events 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 


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• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as 
serious 
• 
Investigator assessment of the association 
between the event and study treatment 
8.3.1 
Investigator reporting: notifying the study sponsor 
  
The following describes events that must be reported to the study sponsor in an expedited fashion. 
 
Initial Report: within 24 hours: 
The following events must be reported to the study sponsor by telephone within 24 hours of awareness of 
the event:  
• 
Unanticipated problems related to study participation,  
• 
Serious adverse events, regardless of whether they are unexpected.  
Additionally, an FDA Form 3500A (MEDWATCH Form; see Attachment VIII) must be completed by the 
investigator and faxed to the study sponsor within 24 hours.  The investigator shall maintain a copy of the 
MEDWATCH Form on file at the study site.  
   
NYU Langone Health 
Division of Rheumatology, Department of Medicine 
NYU Langone Orthopedic Center 
333 East 38th Street, Fourth Floor 
New York, NY 10016 
646-501-7194Telephone 
646-501-7334 Facsimile  
 
Follow-up report: within 48 hours: 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated device event or the unanticipated 
problem in the form of a written narrative.  This should include a copy of the completed Unanticipated 
Problem form, and any other diagnostic information that will assist the understanding of the event.  
Significant new information on ongoing unanticipated adverse device effects shall be provided promptly to 
the study sponsor. 
 
Other Reportable events: 
• 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval 
before they are initiated. Any protocol deviations initiated without Sponsor and the investigator’s 
IRB approval that may affect the scientific soundness of the study, or affect the rights, safety, or 
welfare of study subjects, must be reported to the Sponsor and to the investigator’s IRB as soon 
as a possible, but no later than 5 working days of the protocol deviation awareness. 
 
• 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing 
IRB as soon as a possible, but no later than 5 working days of the IRB notification of withdrawal 
of approval. 
8.3.2 
Investigator reporting: notifying the IRB 
 


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Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, 
though Investigators at participating sites are responsible for meeting the specific requirements of their 
IRB of record.  
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the investigator becomes aware of the event: 
• 
Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be 
caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations 
from the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in 
terms of severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a 
more severe or frequent side effect; Other research finds arm of study has no therapeutic value; 
FDA labeling change or withdrawal from market) 
 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event Form” or 
as a written report of the event (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other 
study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
8.3.3 
Sponsor reporting: Notifying the FDA  
 
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  These 
written notifications of adverse events are referred to as IND safety reports. The following describes the 
safety reporting requirements by timeline for reporting and associated type of event: 
 


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• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity, 
or carcinogenicity. 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A (MEDWATCH Form (see Appendix VIII), or in a 
narrative format. If supplied as in a narrative format, the minimum information to be supplied is noted 
above at the beginning of section 8.3. The contact information for submitting IND safety reports is noted 
below: 
Diana L. Walker, Ph.D., RAC 
Sr. Regulatory Health Project Manager 
FDA/CDER/ODE II/DAAAP 
Tel: 301-796-4029 
Email: Diana.Walker@fda.hhs.gov 
 
8.4 
Unblinding Procedures 
 
Unblinding will be used in the case of any SAE which may be associated with the study drug.  
8.5 
Stopping Rules  
 
Because the study drug is already used clinically in patients at higher risk than the subjects in this study, 
the study is only 3 months long, and because the anticipated rate of adverse events is low, we do not 
anticipate the need to interrupt or stop the study. Nevertheless, a Data Monitoring Committee will be 
created and can determine the need to interrupt or stop the study if necessary.     
 
Subjects are free to discontinue the study at any time.  
8.6 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see 
section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular assessment of 
the number and type of serious adverse events. In addition, the principal investigator will designate an 


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independent safety monitor to make determinations about the nature of any adverse events. This 
individual will conduct his or her review every 6 months and the information will be shared with the PI and 
the study team. 
8.6.1 
Data Monitoring Committee 
 
There is no need for a Data Monitoring Committee. However, monitoring the study is a critical part of its 
success.  Therefore, an internal clinical practitioners (to be determined) will be monitoring the study on a 
biannual basis.  This monitor will work with our clinical and regulatory study teams to ensure that all 
procedures and assessments are being conducted in compliance with the protocol and the informed 
consent. 
9 
Sample Storage, Data Handling, and Record Keeping 
9.1 
Confidentiality 
 
Primary research data will be stored at the NYU Langone Orthropedic Center (LOC).  The sample collection 
includes: synovial fluid, plasma, and serum samples. Subjects will mark in the consent form whether or not 
they agree to provide a synovial fluid sample. These samples will be stored at the Immunology Lab at the 
NYU Langone Orthopedic Hospital located at 301 East 17th Street, Rm 1600, New York, NY 10003). The 
Immunology Lab is managed by Dr. Mukundan Attur.  The samples will be stored for a maximum of over 
20 years unless the patient requests, in writing, for the samples to be destroyed. If patients choose to 
withdraw from the study, as delineated in the consent form, they can write a letter to the study team 
formalizing this request. Samples will immediately be destroyed for patients who wish to withdraw their 
information from the study, and their request for withdrawal will be kept on file by the study team as part of 
documentation for the study records.  
 
“True” genetic testing will not be done.  
 
It is believed the maximum allowance for time to hold samples will allow for significant analysis and 
improvement in understanding surrounding rheumatic disease. Source documents will be stored in study 
binders, which will remain in a locked room/cabinet at the study facility. All subjects will be assigned a 
unique four-digit study number and all subsequent questionnaires and samples will only be encoded with 
this numeric code and the date of collection. A link between patient name, contact information, and identifier 
will be retained by Dr. Pillinger and the study team. These will be retained in a password-protected database 
with original CRFs retained in a locked cabinet in case report binders at LOC. The clinical database will be 
kept in a de-identified, password-protected secure online REDCap database, created for this study. Only 
the principal investigators, co-investigators, and study coordinators will have access to this data. 
Information with subject names will not be used in any publications resulting from this investigation.  
 
For patients who are fully eligible, do not withdraw from the study or request that their samples be 
withdrawn, sample storage for future research is not optional and is a mandatory part of this research. While 
the study team plans to measure certain blood markers soon after each subject is enrolled in the study, 
stored samples would allow for further analysis as the understanding of osteoarthritis changes in the future. 
 
When patient blood and questionnaires are obtained, they will be labeled with the appropriate unique 
numeric code and date of collection. All subsequent data analysis, specimen recording and samples will 
only be encoded with this numeric code and the date of collection. There will be no link between the 
informed consent forms and the subjects' samples.  
 
Chart reviews will require patient names. However, when the data is transferred from patient charts and 
medical questionnaires to the database, only the appropriate numeric code will be used as an identifier.  
 
Serum/plasma will be collected from the study subjects. These samples will be stored in sterile plastic 
tubes in storage containers in locked –80oC freezers in a locked room, and will be accessible only to 


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authorized study personnel. All stored samples will be identified by unique numeric codes and dates of 
collection only, and stored at the Immunology Lab on the 16th Floor at the NYU Langone Orthopedic 
Hospital located at 301 East17th Street, Suite 1600, New York, NY 10003. There is no PHI associated 
with any of the biospecimens for this study. Samples will be stored for future research for up to 20 years. 
Subjects may also decline to participate in having samples banked for future research.    
9.2 
Confidentiality and HIPAA 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
9.3 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
9.4 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is 
left blank because the procedure was not done or the question was not asked, write “N/D”.  If the item is 
not applicable to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any 
entry error has been made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
9.5 
Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a longer 
period if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained.  
 


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10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan in Appendix VI.  The investigator will 
allocate adequate time for such monitoring activities.  The Investigator will also ensure that the monitor or 
other compliance or quality assurance reviewer is given access to all the above noted study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate 
space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
 
11 Ethical Considerations 
 
This study will be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice (GCP), and applicable institutional research policies and procedures. 
In addition to standard trainings, the PI (Michael Pillinger, MD) will participate in PINDAR, NYULMC's GCP 
training for PIs. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board 
(IRB) in agreement with local legal prescriptions, for formal approval of the study conduct. The decision of 
the IRB concerning the conduct of the study will be made in writing to the investigator and a copy of this 
decision will be provided to the sponsor before commencement of this study. The investigator should 
provide a list of IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This consent 
form will be submitted with the protocol for review and approval by the IRB for the study. The formal consent 
of a subject, using the IRB-approved consent form, will be obtained before that subject undergoes any 
study procedure. The consent form will be signed by the subject and the investigator-designated research 
professional obtaining the consent.  
 
Informed consent will be obtained by the Principal Investigator or a designee such as a sub-investigator, 
research coordinator or research nurse.  Any future participants in the consent process will be trained by 
the PIs and the Institution and will be placed on the protocol with IRB approval. The informed consent form 
will be discussed in depth by the individual obtaining consent, with initialing of the subject at each juncture 
to confirm understanding. Complete consent forms will be stored in each subject’s individual binder on site 
at CMC, maintained in a secure cabinet/room. 
 
Before the study starts, one of the investigators or research physician/personnel shall explain the full details 
of the protocol and study procedures as well as risks involved to patients prior to their enrollment in the 
study. Participants will be informed that they are free to withdraw from the study at any time. All participants 
will sign an IRB-approved consent form. Only patients who can consent for themselves and have the 
capacity to do so will be eligible for enrollment in this study. 
 


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12 Study Finances 
12.1 Funding Source 
 
Subjects will incur no undue costs as a result of participation in the study. The study procedures, study drug 
and placebo are financed by Hikma Pharmaceuticals.   
 
12.2 Conflict of Interest 
 
At the present time no investigator has a conflict of interest with this study.  If, in the future, any investigator 
develops a conflict or potential conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.), they will submit the conflict for review by 
a properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to participation in this study. All 
NYULMC investigators will follow the applicable University conflict of interest policies. 
 
12.3 Subject Stipends or Payments 
 
Subjects will receive $50.00 at each of the visits, for a total stipend of $200.00 as compensation for their 
time participating in the study. Subject who are required to come in for the final serum pregnancy visit will 
receive an additional $50.00 for a total of $250.00. The funds for each visit will be sent to the subject via 
ClinCard direct deposit.  
 
13 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study sponsor and company/funding source (Hikma 
Pharmaceuticals).  Any investigator involved with this study is obligated to provide Hikma 
Pharmaceuticals with complete test results and all data derived from the study. 
 
14 References 
 
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Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the 
United States. Part II. Arthritis Rheum 2008;58(1):26-35. 
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Abramson SB, Attur M, Yazici Y. Prospects for disease modification in osteoarthritis. Nat Clin Pract 
Rheumatol 2006; 2(6):304-12. 
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Attur M, et al. Increased interleukin-1beta gene expression in peripheral blood leukocytes is 
associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. 
Arthritis Rheum 2011; 63(7):1908-17. 
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Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). 
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Denoble AE, et al. Uric acid is a danger signal of increasing risk for osteoarthritis through 
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Attur M, et al. Elevated Expression of Inflammatory Mediators Cyclooxygenase-2, Its Product 
Prostaglandin E2 and Interleukin-1 Beta by Peripheral Blood Leukocytes in Symptomatic Knee 
Osteoarthritis. Arthritis Rheum 2011; 63 (S10): S61-S62. 
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Attur M, et al. Interleukin-1 Receptor Antagonist (IL-1Ra) Plasma Levels Predict Radiographic 
Progression of Symptomatic Knee Osteoarthritis Over 24 Months. Arthritis Rheum 2013; 65 
(S10):S804-S804. 
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Ding C, et al. Do NSAIDs affect longitudinal changes in knee cartilage volume and knee cartilage 
defects in older adults? Am J Med. 2009 Sep;122(9):836-42. 
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Nowatzky J, et al. The Role of Uric Acid and Other Crystals in Osteoarthritis. Curr Rheumatol Rep. 
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Muehleman C, et al.: Association between crystals and cartilage degeneration in the ankle. J 
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Ottaviani S, et al. Usefulness of ultrasonography for gout. Joint Bone Spine. 2012 Oct;79(5):441-5. 
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Martinon F, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 
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Liu R, et al.: Proline-rich tyrosine kinase 2 and Src kinase signaling transduce monosodium urate 
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Arthritis Rheum 2004, 50:247–258.  
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Abramson SB: Nitric oxide in inflammation and pain associated with osteoarthritis. Arthritis Res Ther 
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Howard RG, Samuels J, Gyftopoulos S, Krasnokutsky S, Leung J, Swearingen CJ, Pillinger MH. 
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Men. Submitted. Journal of Clinical Rheumatology. 
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Slobodnick A, Shah B, Pillinger MH, Krasnokutsky S. Colchicine: Old and New. Submitted. American 
Journal of Medicine.  
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Taylor EW. The Mechanism of Colchicine Inhibition of Mitosis. I. Kinetics of Inhibition and the Binding 
of H3-Colchicine. J. Cell Biol. 1965;25:suppl:145–60. 
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Cronstein BN, et al. Colchicine alters the quantitative and qualitative display of selectins on 
endothelial cells and neutrophils. J. Clin. Invest. 1995;96(2):994–1002. 
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Terkeltaub RA. Colchicine update: 2008. Semin. Arthritis Rheum. 2009;38(6):411–9. 
24. 
Crittenden, D.B., et al., Colchicine use is associated with decreased prevalence of myocardial 
infarction in patients with gout. J Rheumatol, 2012. 39(7): p. 1458-64. 
25. 
Aran S, et al. A double-blind randomized controlled trial appraising the symptom-modifying effects of 
colchicine on osteoarthritis of the knee. Clin Exp Rheumatol. 2011;29(3):513-8. 
26. 
Das SK, et al. A randomized controlled trial to evaluate the slow-acting symptom-modifying effects of 
colchicine in osteoarthritis of the knee: a preliminary report. Arthritis Rheum. 2002;47(3):280-4. 
27. 
Das SK, et al. A randomized controlled trial to evaluate the slow-acting symptom modifying effects of 
a regimen containing colchicine in a subset of patients with osteoarthritis of the knee. Osteoarthritis 
Cartilage. 2002;10(4):247-52.  
28. 
Altman RD and Gold GE. Atlas of individual radiographic features in osteoarthritis, revised. 
Osteoarthritis Cartilage 2007;15 (Supplement 1): A1–A56. 
29. 
Nidorf SM. Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease. J Am Coll 
Cardiol 2013;60(4):404-410.  
30. 
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR 
and the 2(-Delta Delta C(T)) Method. Methods 2001; 25(4):402-8. 
31.   Kraus VB, et al. Urea as a passive transport marker for arthritis biomarker studies. Arthritis & Rheum 
2002;46(2): 420-427. 
32.  Vignon E, et al. Alignment of the medial tibial plateau affects the rate of joint space narrowing in the 
osteoarthritic knee. Osteoarthritis Cartilage 2010; 18(11):1436-1440. 
 
33.  Thiele RG, Schlesinger N. Diagnosis of gout by ultrasound. Rheumatology 2007; 46(7): 1116-21. 
34.  Cleveland, WS. Robust locally weighted regression and smoothing scatterplots, Journal of the 
American Statistical Association.1979; 368:829-836 


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35.  Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute 
gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-
controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010; 62(4):1060-8.  
36. 
Karatza E, Ismailos G & Karalis V. Colchicine for the treatment of COVID-19 patients: efficacy, safety, 
and model informed dosage regimens. Xenobiotica. 2021; 51:6, 643-656. 
 
15 APPENDICIES 
 
APPENDIX I: Subject Diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX II: Medications That May Interact with Colchicine* 
 
Strong CYP3A4 Inhibitors 
Moderate CYP3A4 Inhibitors 
P-gp Inhibitors 
atazanivir 
amiodarone 
cyclosporine 
boceprevir 
amlodipine 
ranolazine 
clarithromycin 
amprenavir 
omeprazole 
danazol 
aprepitant 
lansoprazole 
gemfibrozil 
atorvastatin 
pantoprazole 
indinavir 
azithromycin 
 
itraconazole 
diltiazem 
 
ketoconazole 
erythromycin 
 
nefazodone 
fluconazole 
 
nelfinavir 
fosamprenavir 
 
ritonavir 
grapefruit juice 
 
saquinavir 
nicotinic acid 
 
telaprevir 
simvastatin 
 


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telithromycin 
verapamil 
 
*Note that some compounds inhibit both CyP3A4 and P-gp.  For simplicity these are listed among the 
CYP3A4 inhibitors and not repeated in the P-gp column. 
 
 
APPENDIX III: Medication Compliance Form (to be provided by Pharmacy) 
 
APPENDIX IV: Drug Reconciliation Form (to be provided by Pharmacy) 
 
APPENDIX V: Ultrasonography Form  
 
For evaluating the knees by ultrasound, there is no gold standard method in the literature.  
Thus we will capture 5 semiquantitative scores on a scale of 0-3 (see below) for osteoarthritis, and 3 yes/no 
questions about crystal disease.  
 
1)    Size of effusion in the anterior suprapatellar space in the longitudinal view, anechoic and 
compressible, on a scale of 0-3 (by millimeter cutoffs) 
2)    Degree of synovial hypertrophy (by gray scale) in the anterior suprapatellar space in the 
longitudinal view, hypoechoic and NOT compressible, on a scale of 0-3 
3)    Degree of synovitis by Doppler signal in the anterior suprapatellar space in the longitudinal 
view,  on a scale of 0-3 (none, scattered, less than 50%, greater than 50% of the area)  
4)    Size of osteophytes in the medial or lateral joint lines (whichever more severe) in the longitudinal 
view, hyperechoic, on a scale of 0-3  
5)    Degree of femoral articular cartilage (FAC) wear in the suprapatellar transverse view with knee 
flexed, on a scale of 0-3 
6)    FAC double contour sign (hyperechoic line across top of anechoic FAC) in the suprapatellar 
transverse view with knee flexed:  yes/no 
7)    FAC evidence of CPPD (hyperechoic deposits in the middle of the anechoic FAC) in the 
suprapatellar transverse view with knee flexed: yes/no 
8)    meniscal evidence of CPPD (hyperechoic deposits in the triangular meniscus edges) in the 
medial and/or latera joint line:   yes/no 
 


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APPENDIX VI: Data Safety Monitoring Plan 
 
1. Types of Data or Events: 
All data collected under the study and schedule of events will be monitored and reviewed by PI and 
Hikma Pharmaceuticals (funding source). 
 
Events that would be specifically reviewed by the DSMP would be those adverse events that are 
known to be associated with colchicine use at the dose ranged tested.   
Adverse events include:  
• 
GI upset  
• 
Soft stools/Diarrhea  
• 
Occassional nausea/vomiting  
In most cases at the dose being tested, these symptoms would be mild. Events that occur with an 
overdose of colchicine could include neuropathy, myopathy, rhabdomyolysis, renal and bone marrow 
failure. However, this is unexpected at the doses tested in this study with the exclusion criteria. The 
occurrence of these at the doses and in the manner we are using the agent would be very rare as too 
be reportable. They are not a concern, but they would be reviewed by the DSMP if they did occur. The 
occurrence of any other unexpected events will also be noted.  
 
 
2. Responsibilities and roles for gathering, evaluating and monitoring the data: 
• 
The PI and study staff will collect the required data and record and monitor all adverse events in a 
timely manner after each participant visit.  Any unanticipated problems, SAEs or events meeting 
reportable IRB criteria will be submitted as per IRB and sponsor guidelines.  
• 
The roles of the investigators, research coordinators at the site will be documented on the 
delegation list for the study and signed by the PI. 
• 
Data accuracy will be monitored by the PI and/or primary data and safety monitor or designee 
upon first subject enrolled and every 3 months as needed. The safety monitor will conduct a 
review of adverse events biannually. 
• 
The primary data and safety monitor or designee will verify compliance with the protocol by 
comparing source documents to research case report forms for accuracy. Monitoring will occur 
upon first subject enrolled and biannually throughout the study.. 
3. Information about the monitoring entity: 
The PI will serve as the monitoring entity and is responsible for the data safety monitoring of the 
overall study, which is deemed appropriate due to: 
• 
the study is conducted at one site only 
• 
the narrow range of possible study events that could occur, supported by the FDA approval of 
the drug 
4. Reporting adverse events and unanticipated problems to the monitoring entity: 
• 
All adverse events will be recorded and followed by study staff/PI. They will be reported if they 
meet IRB and sponsor guidelines for reporting within specified time frame. 
• 
Specific forms or electronic submission will be used to report the events if they meet reporting 
criteria. 
• 
The coordinator will prepare and submit the form signed by PI. 
5. Assessments: 


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The PI will be monitoring the safety and efficacy variables throughout the study, monthly, on all 120 
subjects.  Monitoring will include source data matches entered data and protocol compliance.  Events 
meeting reporting criteria as “unanticipated problems involving risks to participants or others” (i.e., as 
to whether they are unexpected, related and harmful) will be reported to IRB and sponsor. 
 
6. Criteria for action: 
• 
The PI will determine if there is additional action required during study for postponing treatment or 
withdrawal from study.  This would be related to infections or new diagnosis or treatment in which 
study treatment would cause harm. 
• 
Stopping rules will be determined by PI in cases of infection, hospitalizations, voluntary or PI 
withdrawal of subject. 
7. Procedures for Communicating – dissemination of safety information 
As appropriate:  Electronically 
• 
Outcomes of monitoring entity reviews if needed will be provided electronically for communication 
to the IRB and/or research sponsor as needed. 
 
APPENDIX VII: Schedule of Events 
 
Table of Study Visits/Procedures (Appendix VII) 
Procedures/ 
Assessments 
Screening 
Baseline 
Visit 1/Week 6 / 
Day 42-1 
 
Visit 2/Week 12/ 
Day 84 1 
 / Early 
Termination 
/ Termination 
Visit 
Visit 3/Week 
16/Day 112 1 
28 days post 
dosing visit 
Windows 
 
(within 21 days 
from 
Screening) 
±7 days 
±3 days 
 
Informed consent 
X 
 
 
 
 
Inclusion/exclusion 
assessment 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Medical history and 
review 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
Height and Weight 
X 
X 
X 
X 
 
Bilateral Physical 
Knee Exam  
X 
 
 
X 
 
Dispensation by 
Pharmacy 
 
X 
 
 
 
Pill Count 
 
 
X 
X 
 
Bilateral VAS pain 
Questionnaire  
X 
X 
X 
X 
 
KOOS Questionnaire 
for Signal Knee 
 
 
X 
X 
X 
 
Review of Subject 
 
X 
X 
X 
 


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Diary 
Pain in other joints 
(questionnaire) 
 
X 
 
X 
 
Bilateral Knee 
ultrasonography (see 
Appendix V) 
X 
 
 
X 
 
Bilateral Knee x-rays 
 
X 
 
 
 
 
Blood sample 
(complete metabolic 
profile - NYU Lab) 
X 
 
 
X 
 
Blood sample 
(complete blood count 
with diff -NYU Lab) 
X 
 
 
X 
 
Serum Pregnancy (as 
appropriate) 
X 
 
X 
X 
X 
 
Blood Samples (LOH 
Research Lab) 
 
X 
 
X 
 
Synovial fluid sample 
X 
 
 
X 
 
Concomitant Meds 
X 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
 
**Knee x-ray will be performed if subject has not had one within the past 12 months at NYU Langone 
Health. 
 
 
 


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APPENDIX VIII: FDA MEDWATCH FORM 3500A 


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