Effect of Oral Cimetidine in the Protoporphyrias

Phase 2CompletedNCT05020184

Amy K. Dickey, M.D.26 enrolled

Overview

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) result from genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. The objective of this study is to determine the efficacy and safety of oral cimetidine administration for treatment of the protoporphyrias. Efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires. Funding Source- FDA OOPD

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. EPP and XLP, collectively called the protoporphyrias, result in the accumulation of the light-sensitive molecule protoporphyrin IX initially in the bone marrow during hemoglobin synthesis and secondarily in erythrocytes, plasma, and the liver. In addition to photosensitivity, protoporphyria can also result in anemia, gallstones, and liver failure. No therapy has been demonstrated to reduce protoporphyrin levels or prevent the potentially life-threatening complications of EPP. Cimetidine has gained attention as a possible treatment for human porphyrias because of a potential off-target effect of inhibition of delta-aminolevulinate synthase (ALAS), the first enzyme of heme biosynthesis. This inhibition was first described in vitro; however, case reports of benefit in EPP have been anecdotal and uncontrolled. Therefore, the objective of this study is to determine the efficacy and safety of oral cimetidine administration in the protoporphyrias. Efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires. If the results are positive, this would be the first study providing quality evidence for an agent acting as a disease-modifying therapy for EPP. The study is also attractive because it repurposes an already approved drug with few side effects to treat a rare human disease. The study design is a prospective, blinded, randomized, 2x2 cross-over design comparing cimetidine to placebo in patients with protoporphyria. Eligible protoporphyria patients will be randomized with equal allocation to one of two treatment sequences that will be administered over two 3-month study periods. Randomization will be stratified by site and permuted block randomization will be used to prevent chronological bias. Patients randomized to sequence 1 will receive placebo during period 1 and cimetidine during period 2. Patients randomized to sequence 2 will receive cimetidine during period 1 and placebo during period 2. Between periods, to eliminate any carry-over effects from the treatment administered in period 1, a wash-out period of 3 months will occur in which all patients receive neither cimetidine nor placebo. Three months was selected for each study period and for the wash-out period because of the rapid decline in protoporphyrin in red cells over the lifespan of the red cell (120 days), as well as to account for the time frame needed to measure light sensitivity in EPP.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Erythropoietic Protoporphyria X-linked Protoporphyria

Interventions

CimetidineDRUG

Oral Cimetidine 800mg twice daily.

PlaceboDRUG

Placebo twice daily

Eligibility

Sex: ALLMin age: 15 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Prior enrollment or co-enrollment in the Longitudinal Study of the Porphyrias (PC Study 7201) with a confirmed diagnosis of EPP or XLP * Male or female age ≥15 years at screening * Characteristic history of non-blistering cutaneous photosensitivity * Willing and capable of giving informed consent and following procedures described in the protocol Exclusion Criteria: * Participants not willing to expose themselves to light to the point of prodromal symptoms at least weekly * History of liver or bone marrow transplant or clinically significant liver dysfunction as determined by the Investigator * Known or suspected allergy or intolerance to cimetidine * Use of any other experimental therapy in the past 3 months at screening * Use of cimetidine within the past 3 months at screening * Individuals with elevations of porphyrins in plasma or erythrocytes due to other diseases (i.e., secondary porphyrinemia) such as liver and bone marrow diseases * Patients with any clinically significant comorbid conditions, which in the opinion of the Investigator, precludes participation * Treatment with any drugs or supplements (Appendix 1) that in the opinion of the Investigator can interfere with subject safety or the objectives of the study * The participant either does not have a smartphone or is not willing to use his/her smartphone for the study * Women who are pregnant, breastfeeding, or actively planning to become pregnant * Individuals with moderate to severe renal insufficiency

Locations (3)

Massachusetts General Hospital

Boston, Massachusetts, United States

Atrium Health Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, United States

University of Texas Medical Branch

Galveston, Texas, United States

Outcomes

Primary Outcomes

Percent Change in Erythrocyte Total Protoporphyrin Level

Percent change in erythrocyte total protoporphyrin levels after treatment period versus before.

Time frame: Before and after each 3-month treatment period

Secondary Outcomes

Time to Prodrome

Mean daily self-reported outdoor time, in minutes, before EPP/XLP prodrome onset during the last two months of each treatment period, including days without symptoms.

Time frame: Last 2 months of each treatment period

Change in PROMIS-57 v2 Domain T-scores From Pre-treatment to End of Each 3-month Treatment Period

PROMIS-57 v2 assesses 7 health domains: Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference. Domain scores are converted to standardized T-scores with a U.S. general population mean of 50 and standard deviation of 10. Higher scores indicate worse outcomes for Anxiety, Depression, Fatigue, Sleep Disturbance, and Pain Interference, and better outcomes for Physical Function and Ability to Participate in Social Roles and Activities. PROMIS-57 v2 was administered immediately before and at the end of each 3-month treatment period. End-of-period PROMIS-57 v2 domain T-scores were analyzed using mixed-effects linear models adjusted for the immediately pre-treatment PROMIS-57 v2 domain T-score for that treatment period, with treatment as a fixed effect and participant as a random effect. Reported values represent least squared means for change in T-score for the cimetidine and placebo treatment periods.

Time frame: Immediately before and at the end of the 3-month cimetidine treatment period, and immediately before and at the end of the 3-month placebo treatment period

Change in PROMIS-57 v2 Pain Intensity Scores From Pre-treatment to End of Each 3-month Treatment Period

PROMIS-57 v2 Pain Intensity is a single item scored from 0 to 10, with higher scores indicating worse pain intensity. The instrument-defined possible score range is 0 to 10. This question was administered immediately before and at the end of each 3-month treatment period in this crossover trial. End-of-period PROMIS-57 v2 Pain Intensity scores were analyzed using mixed-effects linear models adjusted for the immediately pre-treatment Pain Intensity score for that treatment period, with treatment as a fixed effect and participant as a random effect. Reported values represent least squared means for change in Pain Intensity scores for the cimetidine and placebo treatment periods.

Data from ClinicalTrials.gov

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