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

Trial Summary

What is the purpose of this trial?

Many people develop joint pain, stiffness and swelling due to their cancer treatment that targets the immune system. The severity of symptoms ranges from mild to debilitating and sometimes requires delaying or stopping cancer treatment. The usual plan is to discontinue cancer treatment and give relatively high doses of a medication called prednisone (a steroid, which is an anti-inflammatory medication which may suppress the immune system) with a gradual lowering of the dose over several weeks. While this can be effective, prednisone can cause a number of side effects, and it is not known if this is the best or safest treatment. Hydroxychloroquine is a medication that is often used to treat inflammatory joint pain, such as rheumatoid arthritis, has relatively few side effects when compared to prednisone, and may be effective at treating this condition. The purpose of this study is to find out whether it is better to receive hydroxychloroquine and prednisone, or prednisone alone for joint pain. To do this, some participants will get hydroxychloroquine and some will receive a placebo (a substance that looks like the study drug but does not have any active or medicinal ingredients). A placebo is used to make the results of the study more reliable. This is a double-blinded study, which means that neither participants nor the study doctor or study staff will know which group participants are allocated. After 12 weeks of study treatment, the blind will be opened and participants will be informed which treatment was given.

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.

What evidence supports the effectiveness of the drug hydroxychloroquine for joint pain?

Research shows that hydroxychloroquine is effective in reducing symptoms in conditions like rheumatoid arthritis and systemic lupus erythematosus, which often involve joint pain. It is well-tolerated and can help decrease disease activity and inflammation. ^{1 2 3 4 5}

Is hydroxychloroquine safe for humans?

Hydroxychloroquine is generally considered safe, but it can cause side effects like skin rashes, eye problems, and stomach issues. Rarely, it can lead to severe skin reactions or heart and eye problems, so it's important to monitor for these effects. ^{2 6 7 8 9}

How is the drug hydroxychloroquine unique in treating joint pain?

Hydroxychloroquine is unique because it is traditionally used to treat inflammation in conditions like rheumatoid arthritis and lupus, and it may help reduce joint pain by targeting synovitis (inflammation of the joint lining) in osteoarthritis, which is not commonly addressed by other treatments. ^{1 10 11 12 13}

Research Team

Michael Kolinsky

Principal Investigator

AHS-CCI

Eligibility Criteria

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 18 years old or older.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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, 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]

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]

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]

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]

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]

References

1. Canada pubmed.ncbi.nlm.nih.gov

Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Rheumatoid arthritis. New developments in treatment. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Relationship of cytochrome P450 gene polymorphisms with blood concentrations of hydroxychloroquine and its metabolites and adverse drug reactions. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Combination therapy with gold and hydroxychloroquine in rheumatoid arthritis: a prospective, randomized, placebo-controlled study. [2019]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

The biological and clinical activity of anti-malarial drugs in autoimmune disorders. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Retinal toxicity secondary to Plaquenil therapy. [2016]

7. Scotland pubmed.ncbi.nlm.nih.gov

A case of an acute cutaneous drug reaction with hydroxychloroquine. [2018]

8. France pubmed.ncbi.nlm.nih.gov

[Hallucinations during treatment with hydrochloroquine]. [2019]

9. Italy pubmed.ncbi.nlm.nih.gov

The safety profile of hydroxychloroquine: major cutaneous and extracutaneous adverse events. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Association Between Autoantibody Phenotype and Cutaneous Adverse Reactions to Hydroxychloroquine in Dermatomyositis. [2019]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. [2022]

13. United States pubmed.ncbi.nlm.nih.gov

Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients. [2023]