Erythropoietic Protoporphyria, X-linked Protoporphyria
Conditions
Keywords
Erythropoietic Protoporphyria, X-linked Protoporphyria, EPP, Cimetidine, Photosensitivity
Brief summary
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
Detailed description
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.
Interventions
DRUGCimetidine
Oral Cimetidine 800mg twice daily.
DRUGPlacebo
Placebo twice daily
Sponsors
Amy K. Dickey, M.D.
Wake Forest University Health Sciences
The University of Texas Medical Branch, Galveston
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
randomized, double-blind, placebo-controlled
Intervention model description
The study design is a multicenter, prospective, randomized, double-blind, placebo-controlled, crossover trial of oral cimetidine 800mg twice daily versus placebo
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Erythrocyte Total Protoporphyrin Level | Before and after each 3-month treatment period | Percent change in erythrocyte total protoporphyrin levels after treatment period versus before. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Prodrome | Last 2 months of each treatment period | 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. |
| Change in PROMIS-57 v2 Domain T-scores From Pre-treatment to End of Each 3-month Treatment Period | 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 | 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. |
| Change in PROMIS-57 v2 Pain Intensity Scores From Pre-treatment to End of Each 3-month Treatment Period | 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 | 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. |
| Number of Phototoxic Reactions Per Participant During the Last 2 Months of Each Treatment Period | Last 2 months of the 3-month cimetidine treatment period and last 2 months of the 3-month placebo treatment period | For each participant, the number of phototoxic reactions during the last 2 months of each 3-month treatment period was recorded. In this crossover trial, the reported outcome compares the number of phototoxic reactions per patient during cimetidine with the number during placebo. |
| Blue Light Dose | Last 2 months of each treatment period | Average daily outdoor blue light dose before EPP/XLP prodrome onset during the last two months of each treatment period, including days without symptoms. Dose data for the day were excluded if the patient did not wear the dosimeter for the entire day. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAmy K Dickey, MD
Massachusetts General Hospital
PRINCIPAL_INVESTIGATORKarl Anderson, MD
University of Texas
Participant flow
Recruitment details
A total of 26 patients signed the consent form and were therefore considered enrolled. 25 patients were assigned a randomization group.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 49.1 Years STANDARD_DEVIATION 16.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 25 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
| Study Site MGH | 24 Participants |
| Study Site UTMB | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 23 | 0 / 22 |
| other Total, other adverse events | 14 / 24 | 9 / 23 | 3 / 22 |
| serious Total, serious adverse events | 1 / 24 | 1 / 23 | 0 / 22 |
Outcome results
None listed