Approaches to sample size calculation for clinical trials in rare diseases.

Pharm Stat. 2018 05;17(3):214-230

Authors: Miller F, Zohar S, Stallard N, Madan J, Posch M, Hee SW, Pearce M, Vågerö M, Day S

Abstract
We discuss 3 alternative approaches to sample size calculation: traditional sample size calculation based on power to show a statistically significant effect, sample size calculation based on assurance, and sample size based on a decision-theoretic approach. These approaches are compared head-to-head for clinical trial situations in rare diseases. Specifically, we consider 3 case studies of rare diseases (Lyell disease, adult-onset Still disease, and cystic fibrosis) with the aim to plan the sample size for an upcoming clinical trial. We outline in detail the reasonable choice of parameters for these approaches for each of the 3 case studies and calculate sample sizes. We stress that the influence of the input parameters needs to be investigated in all approaches and recommend investigating different sample size approaches before deciding finally on the trial size. Highly influencing for the sample size are choice of treatment effect parameter in all approaches and the parameter for the additional cost of the new treatment in the decision-theoretic approach. These should therefore be discussed extensively.

PMID: 29322632 [PubMed - indexed for MEDLINE]

Large mesenteric lymphangioma in an adult patient: an unusual presentation of a rare disease.

BMJ Case Rep. 2018 Oct 07;2018:

Authors: Wall KC, Schmitz R, Carney JM, Blazer Iii DG

Abstract
Lymphangiomas are most commonly described as a small painless mass in the neck or a vesicular rash in an infant patient. Ninety per cent of cases are diagnosed before the age of 2. Treatment usually involves surgical resection. Intra-abdominal lymphangiomas and mesenteric lymphangiomas, as described in our case report, represent a rare pathology. The exact prevalence of this condition is unclear but it has been suggested in the literature that there have been as few as 820 cases since the 16th century. The clinical presentation is usually subacute and diagnosis made incidentally during a workup of chronic gastrointestinal symptoms. Acute abdominal symptoms, as in our case presentation, are unusual but may be explained by the mass effect of a large intra-abdominal lesion. Cross-sectional imaging is key in preoperative workup and operative planning. Complete surgical resection is recommended and curative in the majority of cases with a low risk of local recurrence.

PMID: 30297495 [PubMed - indexed for MEDLINE]

The 100 000 Genomes Project: bringing whole genome sequencing to the NHS.

BMJ. 2018 04 24;361:k1687

Authors: Turnbull C, Scott RH, Thomas E, Jones L, Murugaesu N, Pretty FB, Halai D, Baple E, Craig C, Hamblin A, Henderson S, Patch C, O'Neill A, Devereau, Smith K, Martin AR, Sosinsky A, McDonagh EM, Sultana R, Mueller M, Smedley D, Toms A, Dinh L, Fowler T, Bale M, Hubbard T, Rendon A, Hill S, Caulfield MJ, 100 000 Genomes Project

PMID: 29691228 [PubMed - indexed for MEDLINE]

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.

N Engl J Med. 2018 11 29;379(22):2131-2139

Authors: Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng CM, Esteves C, Gahl WA, Hamid R, Jacob HJ, Kikani B, Koeller DM, Kohane IS, Lee BH, Loscalzo J, Luo X, McCray AT, Metz TO, Mulvihill JJ, Nelson SF, Palmer CGS, Phillips JA, Pick L, Postlethwait JH, Reuter C, Shashi V, Sweetser DA, Tifft CJ, Walley NM, Wangler MF, Westerfield M, Wheeler MT, Wise AL, Worthey EA, Yamamoto S, Ashley EA, Undiagnosed Diseases Network

Abstract
BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added.
METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care.
RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes.
CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

PMID: 30304647 [PubMed - indexed for MEDLINE]

Patient re-contact after revision of genomic test results: points to consider-a statement of the American College of Medical Genetics and Genomics (ACMG).

Genet Med. 2018 Dec 22;:

Authors: David KL, Best RG, Brenman LM, Bush L, Deignan JL, Flannery D, Hoffman JD, Holm I, Miller DT, O'Leary J, Pyeritz RE, ACMG Social Ethical Legal Issues Committee

Abstract

PMID: 30578420 [PubMed - as supplied by publisher]

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.

BJOG. 2018 Dec 21;:

Authors: Spencer R, Rossi C, Lees M, Peebles D, Brocklehurst P, Martin J, Hansson SR, Hecher K, Marsal K, Figueras F, Gratacos E, David AL, EVERREST Consortium

Abstract
OBJECTIVE: To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10,000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation.
DESIGN: Incidence estimation based on literature review and published national and EU statistics.
SETTING AND POPULATION: European Union.
METHODS: Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched.
RESULTS: The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93% to 3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10,000 EU population (95% CI 3.07 to 3.60 per 10,000 EU population). This fell below the EMA threshold of 5 per 10,000 EU population.
CONCLUSIONS: Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life-threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. This article is protected by copyright. All rights reserved.

PMID: 30576053 [PubMed - as supplied by publisher]

Mitochondrial dysfunction is a key determinant of the rare disease lymphangioleiomyomatosis and provides a novel therapeutic target.

Oncogene. 2018 Dec 20;:

Authors: Abdelwahab EMM, Pal S, Kvell K, Sarosi V, Bai P, Rue R, Krymskaya V, McPhail D, Porter A, Pongracz JE

Abstract
Lymphangioleiomyomatosis (LAM) is a rare and progressive systemic disease affecting mainly young women of childbearing age. A deterioration in lung function is driven by neoplastic growth of atypical smooth muscle-like LAM cells in the pulmonary interstitial space that leads to cystic lung destruction and spontaneous pneumothoraces. Therapeutic options for preventing disease progression are limited and often end with lung transplantation temporarily delaying an inevitable decline. To identify new therapeutic strategies for this crippling orphan disease, we have performed array based and metabolic molecular analysis on patient-derived cell lines. Our results point to the conclusion that mitochondrial biogenesis and mitochondrial dysfunction in LAM cells provide a novel target for treatment.

PMID: 30573768 [PubMed - as supplied by publisher]

Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials.

JAMA. 2018 12 11;320(22):2344-2353

Authors: Stunnenberg BC, Raaphorst J, Groenewoud HM, Statland JM, Griggs RC, Woertman W, Stegeman DF, Timmermans J, Trivedi J, Matthews E, Saris CGJ, Schouwenberg BJ, Drost G, van Engelen BGM, van der Wilt GJ

Abstract
Importance: In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed.
Objective: To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT.
Design, Setting, and Participants: A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016.
Interventions: Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks.
Main Outcomes and Measures: Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference.
Results: Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26).
Conclusions and Relevance: In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.
Trial Registration: ClinicalTrials.gov Identifier: NCT02045667.

PMID: 30535218 [PubMed - indexed for MEDLINE]

Becker's nevus syndrome: a report of a rare disease with unusual associations.

Int J Dermatol. 2017 Apr;56(4):458-460

Authors: Ghosh SK, Majumder B, Agarwal M

PMID: 27655000 [PubMed - indexed for MEDLINE]

Characteristics of undiagnosed diseases network applicants: implications for referring providers.

BMC Health Serv Res. 2018 Aug 22;18(1):652

Authors: Walley NM, Pena LDM, Hooper SR, Cope H, Jiang YH, McConkie-Rosell A, Sanders C, Schoch K, Spillmann RC, Strong K, McCray AT, Mazur P, Esteves C, LeBlanc K, Undiagnosed Diseases Network, Wise AL, Shashi V

Abstract
BACKGROUND: The majority of undiagnosed diseases manifest with objective findings that warrant further investigation. The Undiagnosed Diseases Network (UDN) receives applications from patients whose symptoms and signs have been intractable to diagnosis; however, many UDN applicants are affected primarily by subjective symptoms such as pain and fatigue. We sought to characterize presenting symptoms, referral sources, and demographic factors of applicants to the UDN to identify factors that may determine application outcome and potentially differentiate between those with undiagnosed diseases (with more objective findings) and those who are less likely to have an undiagnosed disease (more subjective symptoms).
METHODS: We used a systematic retrospective review of 151 consecutive Not Accepted and 50 randomly selected Accepted UDN applications. The primary outcome was whether an applicant was Accepted, or Not Accepted, and, if accepted, whether or not a diagnosis was made. Objective and subjective symptoms and information on prior specialty consultations were collected from provider referral letters. Demographic data and decision data on network acceptance were gathered from the UDN online portal.
RESULTS: Fewer objective findings and more subjective symptoms were found in the Not Accepted applications. Not Accepted referrals also were from older individuals, reported a shorter period of illness, and were referred to the UDN by their primary care physicians. All of these differences reached statistical significance in comparison with Accepted applications. The frequency of subspecialty consults for diagnostic purposes prior to UDN application was similar in both groups.
CONCLUSIONS: The preponderance of subjective and lack of objective findings in the Not Accepted applications distinguish these from applicants that are accepted for evaluation and diagnostic efforts through the UDN. Not Accepted applicants are referred primarily by their primary care providers after multiple specialist consultations fail to yield answers. Distinguishing between patients with undiagnosed diseases with objective findings and those with primarily subjective findings can delineate patients who would benefit from further diagnostic processes from those who may have functional disorders and need alternative pathways for management of their symptoms.
TRIAL REGISTRATION: clinicaltrials.gov NCT02450851 , posted May 21st 2015.

PMID: 30134969 [PubMed - indexed for MEDLINE]

Rare disease prevention and treatment: the need for a level playing field.

Pharmacogenomics. 2018 02;19(3):243-247

Authors: Hughes DA, Plumpton CO

Abstract
Pharmacogenetic tests are being used increasingly to prevent rare and potentially life-threatening adverse drug reactions. For many tests, however, cost-effectiveness is hard to demonstrate, and with the exception of a few cases, widespread implementation remains a distant prospect. Many orphan drugs for rare diseases are also not cost effective but are nonetheless normally reimbursed. In this article, we argue that the health technology assessment of pharmacogenetic tests aimed to prevent rare but severe adverse drug reactions should be on a level playing field with orphan drugs. This is supported by a number of arguments, concerning the severity, rarity and iatrogenic nature of adverse drug reactions, the distribution of benefits and costs and societal preference towards prevention over treatment.

PMID: 29327657 [PubMed - indexed for MEDLINE]

Bumps in the Road for Commercial Gene Therapy for Rare Diseases.

Mol Ther. 2017 10 04;25(10):2225

Authors: Ylä-Herttuala S

PMID: 28939088 [PubMed - indexed for MEDLINE]

A Rare Decade Where Magic Could Happen.

PDA J Pharm Sci Technol. 2016 May-Jun;70(3):189-90

Authors: Kondragunta B

PMID: 27252365 [PubMed - indexed for MEDLINE]

Total pericardium agenesis mistaken for arrhythmogenic right ventricular cardiomyopathy.

Eur Heart J Cardiovasc Imaging. 2018 01 01;19(1):120

Authors: Laredo M, Duthoit G, Gandjbakhch E, Redheuil A, Hébert JL

PMID: 29040463 [PubMed - indexed for MEDLINE]

The Role of Real-World Evidence in UK Reimbursement: Case Study of Lenalidomide in Myelodysplastic Syndrome Deletion 5q.

Pharmacoecon Open. 2018 Dec 14;:

Authors: Lee D, Brereton N, Dhanasiri S, Kulasekararaj A

Abstract
BACKGROUND: Uncertainty within cost-effectiveness analysis, often driven by lack of mature data from large clinical trials, plays a key role in decisions made by the National Institute for Health and Care Excellence (NICE), particularly for early access medicines and orphan drugs.
OBJECTIVES: In this case study, we used real-world evidence to address the uncertainty in the cost-effectiveness case for lenalidomide in transfusion-dependent low- and intermediate-1-risk myelodysplastic syndrome (MDS) deletion 5q [del(5q)], affecting a small but unique subpopulation with an orphan disease.
METHODS: As part of a submission to NICE, we developed a cost-effectiveness model for lenalidomide, resulting in eventual recommendation.
RESULTS: Due to data limitations within the trial evidence available, the model was based on surrogate outcomes supported by a disease-wide literature review. The validity of modelled estimates for critical long-term outcomes in terms of time on treatment (32% reaching 26 cycles when the patient access scheme applied in the model vs. 28% in the real-world data) and survival was confirmed using real-world evidence (projected median survival for best supportive care of 4.3 years vs. real-world evidence showing median survival with low- and intermediate-1-risk MDS of 5.7 and 3.5 years, respectively).
CONCLUSION: This case study demonstrates the usefulness and relevance of the application of real-world data when trial data are limited.

PMID: 30552652 [PubMed - as supplied by publisher]

Novel variants in SPTAN1 without epilepsy: An expansion of the phenotype.

Am J Med Genet A. 2018 Dec 11;:

Authors: Gartner V, Markello TC, Macnamara E, De Biase A, Thurm A, Joseph L, Beggs A, Schmahmann JD, Berry GT, Anselm I, Boslet E, Tifft CJ, Gahl WA, Lee PR

Abstract
We describe two unrelated children with de novo variants in the non-erythrocytic alpha-II-spectrin (SPTAN1) gene who have hypoplastic brain structures, intellectual disability, and both fine and gross motor impairments. Using agnostic exome sequencing, we identified a nonsense variant creating a premature stop codon in exon 21 of SPTAN1, and in a second patient we identified an intronic substitution in SPTAN1 prior to exon 50 creating a new donor acceptor site. Neither of these variants has been described previously. Although some of these patients' features are consistent with the known SPTAN1 encephalopathy phenotype, these two children do not have epilepsy, in contrast to reports about nearly every other patient with heterozygous SPTAN1 variants and in all patients with a variant near the C-terminal coding region. Moreover, both children have abnormal thyroid function, which has not been previously reported in association with SPTAN1 variant. We present a detailed discussion of the clinical manifestations of these two unique SPTAN1 variants and provide evidence that both variants result in reduced mRNA expression despite different locations within the gene and clinical phenotypes. These findings expand the motor, cognitive, and behavioral spectrum of the SPTAN1-associated phenotype and invite speculation about underlying pathophysiologies.

PMID: 30548380 [PubMed - as supplied by publisher]

COEXISTENCE OF GASTRIC DIVERTICULUM AND GASTRIC CANCER.

Gastroenterol Nurs. 2018 Mar/Apr;41(2):166-168

Authors: Ölmez S, Aslan M, Yavuz A, Sarıtaş B

PMID: 29596131 [PubMed - indexed for MEDLINE]

Polyamine Homeostasis in Snyder-Robinson Syndrome.

Med Sci (Basel). 2018 Dec 07;6(4):

Authors: Murray-Stewart T, Dunworth M, Foley JR, Schwartz CE, Casero RA

Abstract
Loss-of-function mutations of the spermine synthase gene (SMS) result in Snyder-Robinson Syndrome (SRS), a recessive X-linked syndrome characterized by intellectual disability, osteoporosis, hypotonia, speech abnormalities, kyphoscoliosis, and seizures. As SMS catalyzes the biosynthesis of the polyamine spermine from its precursor spermidine, SMS deficiency causes a lack of spermine with an accumulation of spermidine. As polyamines, spermine, and spermidine play essential cellular roles that require tight homeostatic control to ensure normal cell growth, differentiation, and survival. Using patient-derived lymphoblast cell lines, we sought to comprehensively investigate the effects of SMS deficiency on polyamine homeostatic mechanisms including polyamine biosynthetic and catabolic enzymes, derivatives of the natural polyamines, and polyamine transport activity. In addition to decreased spermine and increased spermidine in SRS cells, ornithine decarboxylase activity and its product putrescine were significantly decreased. Treatment of SRS cells with exogenous spermine revealed that polyamine transport was active, as the cells accumulated spermine, decreased their spermidine level, and established a spermidine-to-spermine ratio within the range of wildtype cells. SRS cells also demonstrated elevated levels of tissue transglutaminase, a change associated with certain neurodegenerative diseases. These studies form a basis for further investigations into the leading biochemical changes and properties of SMS-mutant cells that potentially represent therapeutic targets for the treatment of Snyder-Robinson Syndrome.

PMID: 30544565 [PubMed]

Novel CHM mutations in Polish patients with choroideremia - an orphan disease with close perspective of treatment.

Orphanet J Rare Dis. 2018 Dec 12;13(1):221

Authors: Skorczyk-Werner A, Wawrocka A, Kochalska N, Krawczynski MR

Abstract
BACKGROUND: Choroideremia (CHM) is a rare X-linked recessive retinal dystrophy characterized by progressive chorioretinal degeneration in the males affected. The symptoms include night blindness in childhood, progressive peripheral vision loss and total blindness in the late stages. The disease is caused by mutations in the CHM gene encoding Rab Escort Protein 1 (REP-1). The aim of the study was to identify the molecular basis of choroideremia in five families of Polish origin.
METHODS: Six male patients from five unrelated families of Polish ethnicity, who were clinically diagnosed with choroideremia, were examined in this study. An ophthalmologic examination performed in all the probands included: best-corrected visual acuity, slit-lamp examination, funduscopy, fluorescein angiography and perimetry. The entire coding region encompassing 15 exons and the flanking intronic sequences of the CHM gene were amplified with PCR and directly sequenced in all the patients.
RESULTS: Five variants in the CHM gene were identified in the five families examined. Two of the variants were new: c.1175dupT and c.83C > G, while three had been previously reported.
CONCLUSIONS: This study provides the first molecular genetic characteristics of patients with choroideremia from the previously unexplored Polish population.

PMID: 30541579 [PubMed - in process]

A rare cause of blanching red legs: cutaneous collagenous vasculopathy.

Int J Dermatol. 2018 Mar;57(3):349-350

Authors: Roy SF, Ghazawi FM, Veilleux B, Bouffard D, Bélisle A

PMID: 29359327 [PubMed - indexed for MEDLINE]