A phase II futility trial of Hydroxychloroquine in primary progressive MS. results of the first stage of the trial
ECTRIMS Online Library. Koch M. 09/11/19; 279000; P640
Marcus Koch
Marcus Koch
Contributions
Abstract

Abstract: P640

Type: Poster Sessions

Abstract Category: Therapy - Neuroprotection and Repair

M. Koch1, S. Kaur1, K. Sage1, J. Kim1, G. Cerchiaro1, V.W. Yong1, G. Cutter2, L. Metz1

1Clinical Neurosciences, University of Calgary, Calgary, AB, Canada, 2Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States

Background: Primary progressive multiple sclerosis (PPMS) is characterized by slow and relentless worsening of disability. Neurodegeneration and chronic microglial activation are important features in the pathology of PPMS. Hydroxychloroquine (HCQ) is an antimalarial drug with anti-inflammatory properties that is widely used in the treatment of rheumatological diseases. We reported that HCQ reduces human microglial activation and improves neuronal survival in in-vitro and animal studies. In this phase II clinical trial, we used a MiniMax Simon-Two-Stage futility trial design to investigate the potential of HCQ treatment for reducing disability progression in people with PPMS.
Methods: This trial is an 18 months phase II futility trial. In an effort to represent typical PPMS, we include men and women with PPMS aged 18 to 65, with a screening EDSS score of 4.0 to 6.5 inclusive and a timed 25 foot walk (T25FW) of 5.5 seconds or more. Patients with gadolinium enhancing lesions on a screening MRI are excluded. The primary endpoint is worsening on the T25FW by 20% or more between 6 months and 18 months of follow-up. Based on original trial and natural history data, we expect 40% of the trial cohort to experience clinical worsening. The futility threshold is set at 20% of the trial cohort. Using a type 1 error rate of 5%, and 80% power, the trial requires 35 participants to finish both stages - with this interim analysis performed after 13 participants finish the first stage. HCQ treatment is deemed futile if 5 or more of these 13 participants have clinical worsening. Patients are treated with 200mg of HCQ twice daily for 18 months. Trial Registration: Clinicatrials.gov NCT02913157
Results: 27 patients were screened of whom 19 were enrolled. Six patients terminated the trial early (4 due to initial side effects, and 2 for other reasons, none because of worsening disability). The median age at baseline of the 13 patients who finished the trial was 55 years, 4 (31%) were female, none of the trial participants were using disease modifying drugs. Only 2 of 13 (15%) patients experienced clinical worsening, significantly less than the anticipated historical rate of 40% (p< 0.05).
Discussion: After the first stage of this two stage trial, significantly fewer patients than expected experienced clinical worsening. HCQ treatment was overall well tolerated. HCQ treatment is deemed non-futile at this interim stage of the trial. The trial continues into the second stage.
Disclosure: Marcus Koch: nothing to disclose
Sharanjit Kaur: nothing to disclose
Kayla Sage: nothing to disclose
Janet Kim: nothing to disclose
Graziela Cerchiaro: nothing to disclose
V. Wee Yong: nothing to disclose
Gary Cutter: nothing to disclose
Luanne Metz: nothing to disclose

Abstract: P640

Type: Poster Sessions

Abstract Category: Therapy - Neuroprotection and Repair

M. Koch1, S. Kaur1, K. Sage1, J. Kim1, G. Cerchiaro1, V.W. Yong1, G. Cutter2, L. Metz1

1Clinical Neurosciences, University of Calgary, Calgary, AB, Canada, 2Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States

Background: Primary progressive multiple sclerosis (PPMS) is characterized by slow and relentless worsening of disability. Neurodegeneration and chronic microglial activation are important features in the pathology of PPMS. Hydroxychloroquine (HCQ) is an antimalarial drug with anti-inflammatory properties that is widely used in the treatment of rheumatological diseases. We reported that HCQ reduces human microglial activation and improves neuronal survival in in-vitro and animal studies. In this phase II clinical trial, we used a MiniMax Simon-Two-Stage futility trial design to investigate the potential of HCQ treatment for reducing disability progression in people with PPMS.
Methods: This trial is an 18 months phase II futility trial. In an effort to represent typical PPMS, we include men and women with PPMS aged 18 to 65, with a screening EDSS score of 4.0 to 6.5 inclusive and a timed 25 foot walk (T25FW) of 5.5 seconds or more. Patients with gadolinium enhancing lesions on a screening MRI are excluded. The primary endpoint is worsening on the T25FW by 20% or more between 6 months and 18 months of follow-up. Based on original trial and natural history data, we expect 40% of the trial cohort to experience clinical worsening. The futility threshold is set at 20% of the trial cohort. Using a type 1 error rate of 5%, and 80% power, the trial requires 35 participants to finish both stages - with this interim analysis performed after 13 participants finish the first stage. HCQ treatment is deemed futile if 5 or more of these 13 participants have clinical worsening. Patients are treated with 200mg of HCQ twice daily for 18 months. Trial Registration: Clinicatrials.gov NCT02913157
Results: 27 patients were screened of whom 19 were enrolled. Six patients terminated the trial early (4 due to initial side effects, and 2 for other reasons, none because of worsening disability). The median age at baseline of the 13 patients who finished the trial was 55 years, 4 (31%) were female, none of the trial participants were using disease modifying drugs. Only 2 of 13 (15%) patients experienced clinical worsening, significantly less than the anticipated historical rate of 40% (p< 0.05).
Discussion: After the first stage of this two stage trial, significantly fewer patients than expected experienced clinical worsening. HCQ treatment was overall well tolerated. HCQ treatment is deemed non-futile at this interim stage of the trial. The trial continues into the second stage.
Disclosure: Marcus Koch: nothing to disclose
Sharanjit Kaur: nothing to disclose
Kayla Sage: nothing to disclose
Janet Kim: nothing to disclose
Graziela Cerchiaro: nothing to disclose
V. Wee Yong: nothing to disclose
Gary Cutter: nothing to disclose
Luanne Metz: nothing to disclose

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