Hydroxychloroquine for Joint Pain

(IMPACT 2 Trial)

Overseen By Michael Kolinsky

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Inflammatory arthritis, Cardiovascular disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

46 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if hydroxychloroquine, a medication often used for autoimmune conditions, can reduce joint pain and swelling in individuals undergoing cancer treatment targeting the immune system. Researchers will compare two treatments: one group will receive hydroxychloroquine with prednisone, while another will receive a placebo with prednisone. The study seeks to determine if adding hydroxychloroquine improves outcomes compared to prednisone alone. Individuals who have developed significant joint pain from their cancer treatment may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications. However, it mentions that current use of certain immunosuppressive medications is not allowed, except for specific types like inhaled or topical steroids. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that hydroxychloroquine is generally safe, especially compared to treatments like prednisone. It is often used for conditions such as rheumatoid arthritis and has long been trusted to treat similar joint problems. Most specialists in joint issues consider it safe because its side effects are usually mild, such as an upset stomach or a skin rash, with serious reactions being rare.

In contrast, prednisone, also part of this trial, can have more serious side effects, particularly at high doses. These may include weight gain, mood changes, and increased blood pressure. The study aims to determine if adding hydroxychloroquine can reduce the need for higher doses of prednisone, potentially lowering these side effects.

Overall, while both treatments can have side effects, hydroxychloroquine is generally well-tolerated and has a long history of safe use for joint pain. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about hydroxychloroquine for joint pain because it offers a different approach compared to typical treatments like NSAIDs or biologics. Unlike these standard options, hydroxychloroquine is an antimalarial drug that works by modulating the immune system, potentially reducing inflammation with fewer side effects. Plus, when combined with prednisone, it may provide a synergistic effect, enhancing pain relief and improving joint function. This dual approach could offer a promising alternative for those who do not respond well to existing therapies.

What evidence suggests that hydroxychloroquine might be an effective treatment for joint pain?

Research has shown that hydroxychloroquine often relieves joint pain in conditions like rheumatoid arthritis. In one study, 63% of patients with rheumatoid arthritis experienced improvement after using this treatment, and 12% reported no joint pain at all. However, other studies, such as the OA-TREAT study, found that hydroxychloroquine did not significantly reduce pain for people with osteoarthritis. In this trial, one group of participants will receive hydroxychloroquine with prednisone, while another group will receive a placebo with prednisone. Overall, hydroxychloroquine is known for milder side effects compared to treatments like prednisone, suggesting it could be a promising option for managing joint pain related to cancer treatments. ^{2 3 5 6 7}

Who Is on the Research Team?

Michael Kolinsky

Principal Investigator

AHS-CCI

Are You a Good Fit for This Trial?

This trial is for adults over 18 with cancer-related joint pain from immune therapy, who can consent to treatment and have a decent performance status. They must not have inflammatory arthritis or other conditions needing immunosuppressants, no severe allergies to the study drug, and should follow birth control guidelines.

Inclusion Criteria

I agree not to donate sperm during and for 3 months after the study.

I am able to understand and agree to the study's requirements.

I am a woman who can have children and have a negative pregnancy test.

Exclusion Criteria

My heart's electrical cycle is longer than normal or I take medication that can extend this cycle.

I have been diagnosed with an immune system disorder.

I have experienced side effects from immunotherapy that are moderate or worse, excluding insulin-dependent diabetes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either hydroxychloroquine and prednisone or a placebo and prednisone for joint pain

12 weeks

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Hydroxychloroquine
• Placebo
• Prednisone

Trial Overview The trial tests if Hydroxychloroquine combined with prednisone is better than prednisone alone for treating joint pain caused by cancer immune treatments. Participants are randomly given either Hydroxychloroquine or a placebo without knowing which one they receive.

How Is the Trial Designed?

Group I: Hydroxychloroquine, plus prednisone Experimental Treatment 1 Intervention

Hydroxychloroquine 5mg/kg PO daily, plus prednisone starting at 20 mg PO daily for 8 weeks tapering dose.

Group II: Hydroxychloroquine-matching placebo, plus prednisone Placebo Group 1 Intervention

Matching placebo daily, plus prednisone starting at 20 mg PO daily for 8 weeks tapering dose.

Hydroxychloroquine is already approved in United States, European Union for the following indications:

Approved in United States as Plaquenil for:

• Malaria
• Rheumatoid Arthritis
• Systemic Lupus Erythematosus

Approved in European Union as Plaquenil for:

• Malaria
• Rheumatoid Arthritis
• Systemic Lupus Erythematosus

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Published Research Related to This Trial

In a study of 111 adults with dermatomyositis, 20.7% experienced skin eruptions after starting hydroxychloroquine, indicating a notable risk of adverse reactions in this population.

Patients with anti-SAE-1/2 autoantibodies had a significantly higher risk (50%) of developing skin eruptions, while those with anti-MDA-5 autoantibodies showed a protective effect, suggesting that specific autoantibody profiles can influence the safety of hydroxychloroquine treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Autoantibody Phenotype and Cutaneous Adverse Reactions to Hydroxychloroquine in Dermatomyositis. Wolstencroft, PW., Casciola-Rosen, L., Fiorentino, DF.[2019]

For patients with active rheumatoid arthritis who do not find relief from nonsteroidal anti-inflammatory drugs, it is crucial to start disease-modifying antirheumatic drugs (DMARDs) promptly to manage their condition effectively.

Hydroxychloroquine (Plaquenil) is one of the most commonly used DMARDs due to its good tolerance, but careful monitoring is necessary as all DMARDs can have severe and unpredictable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rheumatoid arthritis. New developments in treatment. Corman, LC.[2019]

The HERO trial will evaluate the efficacy of hydroxychloroquine in reducing pain and synovitis in 252 patients with symptomatic hand osteoarthritis over 12 months, using a randomized, double-blind, placebo-controlled design.

The primary outcome will measure changes in average hand pain at six months, while secondary outcomes will assess function, quality of life, and potential structural benefits, aiming to establish hydroxychloroquine as a practical treatment option for osteoarthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial. Kingsbury, SR., Tharmanathan, P., Adamson, J., et al.[2021]

Hydroxychloroquine, commonly used for rheumatological disorders, has been linked to a variety of adverse effects, particularly in women over 50, with skin rashes being the most common issue occurring within 4 weeks of treatment.

More severe adverse events, although rare, include serious skin reactions like Stevens-Johnson syndrome and systemic issues such as cardiotoxicity and retinopathy, highlighting the importance of monitoring patients on this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety profile of hydroxychloroquine: major cutaneous and extracutaneous adverse events. Gisondi, P., Piaserico, S., Bordin, C., et al.[2022]

In a study of 146 patients with systemic lupus erythematosus and rheumatoid arthritis, specific genetic variations in the CYP450 enzyme (particularly CYP3A4 and CYP3A5) were linked to blood levels of hydroxychloroquine (HCQ) and its metabolites, suggesting that genetic testing could help tailor HCQ therapy.

Certain genotypes of CYP3A5 and CYP2C8 were associated with an increased risk of adverse drug reactions (ADRs), such as skin issues and abnormal renal function, indicating that understanding these genetic factors may improve patient safety and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship of cytochrome P450 gene polymorphisms with blood concentrations of hydroxychloroquine and its metabolites and adverse drug reactions. Gao, B., Tan, T., Cao, X., et al.[2022]

In a 12-month study involving 101 patients with active rheumatoid arthritis, combination therapy of gold and hydroxychloroquine showed a significant overall advantage in clinical outcomes compared to gold and placebo, particularly in reducing C-reactive protein levels.

However, the combination therapy also resulted in a higher rate of withdrawals due to adverse reactions (18 cases) compared to the gold/placebo group (10 cases), indicating a need to balance efficacy with safety in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with gold and hydroxychloroquine in rheumatoid arthritis: a prospective, randomized, placebo-controlled study. Scott, DL., Dawes, PT., Tunn, E., et al.[2019]

In a study involving 18 patients with systemic lupus erythematosus and 13 patients with rheumatoid arthritis, hydroxychloroquine significantly reduced levels of pro-inflammatory cytokines IL-6, IL-17, and IL-22 in immune cells, suggesting its immunomodulatory effects.

These findings enhance our understanding of hydroxychloroquine's mechanism of action beyond its traditional use as an antimalarial agent, indicating its potential role in managing autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients. Silva, JC., Mariz, HA., Rocha, LF., et al.[2023]

Hydroxychloroquine, typically viewed as a safe medication, can cause severe cutaneous adverse drug reactions, as demonstrated in a case involving a 63-year-old male who developed widespread skin eruptions after starting the drug for inflammatory arthritis.

Although such severe reactions are uncommon, this case emphasizes the importance of informing patients about potential skin side effects before starting hydroxychloroquine treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of an acute cutaneous drug reaction with hydroxychloroquine. Randhawa, A., Wylie, G.[2018]

A 75-year-old woman experienced cenesthetic hallucinations and disorientation after 10 days of hydrochloroquine treatment for erosive plantar lichen planus, highlighting a rare neuropsychiatric side effect of the medication.

The patient's psychiatric symptoms resolved within a month after stopping hydrochloroquine, indicating that these side effects may be idiosyncratic and not related to dosage, which is important for clinicians to consider when prescribing this drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hallucinations during treatment with hydrochloroquine]. Ferraro, V., Mantoux, F., Denis, K., et al.[2019]

Hydroxychloroquine (HCQ) and chloroquine (CQ) have been effectively used for over 70 years to treat systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), with HCQ being preferred due to its lower incidence of gastrointestinal and ocular side effects.

Both drugs have multiple mechanisms of action, including the ability to accumulate in immune cells and modulate inflammatory responses, which may also help in reducing cardiovascular risks and improving glycaemia in patients, although their exact mechanisms in vivo remain unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Rainsford, KD., Parke, AL., Clifford-Rashotte, M., et al.[2022]

Chloroquine and hydroxychloroquine are effective in reducing disease progression and exacerbations in autoimmune disorders like systemic lupus erythematosus and rheumatoid arthritis, due to their immunosuppressive properties that lower T-cell and B-cell activity.

Despite their efficacy, the use of chloroquine and hydroxychloroquine is tempered by potential adverse effects, which can limit their effectiveness and safety in treating autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The biological and clinical activity of anti-malarial drugs in autoimmune disorders. Taherian, E., Rao, A., Malemud, CJ., et al.[2019]

In a 48-week study involving 71 patients with mild systemic lupus erythematosus (SLE), hydroxychloroquine (HCQ) was found to be well tolerated and provided significant subjective pain relief compared to placebo, although no other joint measures showed differences.

Despite the positive subjective assessment of joint pain, the study did not find any remissions or significant improvements in other joint-related outcomes, indicating that while HCQ may help with pain, its overall efficacy in treating SLE articular complaints is limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus. Williams, HJ., Egger, MJ., Singer, JZ., et al.[2013]

A 71-year-old woman experienced retinal toxicity after taking hydroxychloroquine for 5 years, highlighting the risk of ocular side effects, particularly toxic maculopathy, associated with this medication.

The only effective treatment for hydroxychloroquine toxicity is to discontinue the drug, but the toxic effects may continue to progress due to the slow clearance of the medication, emphasizing the importance of regular eye examinations before and during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinal toxicity secondary to Plaquenil therapy. Hanna, B., Holdeman, NR., Tang, RA., et al.[2016]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/6346870/

Hydroxychloroquine sulfate in rheumatoid arthritis 63 percent responded: 12 percent achieved complete remission (no joint pain or tenderness, two or less joints with trace swelling); 14 percent showed a 75 ...

2. rmdopen.bmj.com rmdopen.bmj.com/content/7/2/e001660

results of the OA-TREAT study—a randomised, double- ... HCQ was no more effective than PBO for changes in pain, function and radiographic scores in the 52-week period. Overall safety findings were ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0002934399803994

A randomized trial of hydroxychloroquine in early ... At 36 weeks and over the course of the study there was statistically significant improvement in the joint index (P = 0.004, P = 0.034, respectively), the pain ...

4. lupus.org lupus.org/resources/drug-spotlight-on-hydroxychloroquine

Hydroxychloroquine (Plaquenil): Benefits, Side Effects, and ... In 1955 HCQ was shown to be effective for both systemic lupus and rheumatoid arthritis. ... joint pain. Dosing. Hydroxychloroquine is generally prescribed at a ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8747931/

Efficacy and safety of hydroxychloroquine in osteoarthritis Conclusions. HCQ has no benefit in reducing pain and improving physical function in hand or knee OA patients. Keywords: Hydroxychloroquine, Osteoarthritis, ...

6. mayoclinic.org mayoclinic.org/drugs-supplements/hydroxychloroquine-oral-route/description/drg-20064216

Hydroxychloroquine (oral route) - Side effects & dosage Safety and efficacy of hydroxychloroquine to treat lupus and arthritis have not been established in children.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/0002934383912706

Hydroxychloroquine sulfate in rheumatoid arthritis 63 percent responded: 12 percent achieved complete remission (no joint pain or tenderness, two or less joints with trace swelling); 14 percent showed a 75 ...