Goal 2: Reduce Human Disease

Interstitial Lung Disease

Is FVC a valid surrogate for mortality in patients with idiopathic pulmonary disease?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

This question is central to all future clinical research in the field and MUST be answered in the context of an interventional clinical trial. Longitudinal cohort studies correlating FVC change with survival are insufficient. The intervention that would make the most sense to test currently is pirfenidone. It is approved for use in many countries and many experts (including the submitter of this compelling question) believe it is likely effective. A mortality-driven clinical trial of pirfenidone vs. placebo would address this question directly, as well as determine the true impact of pirfenidone on clinically meaningful endpoints.

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Goal 2: Reduce Human Disease

Interstitial Lung Disease

Does prednisone therapy improve outcomes in acute exacerbation of IPF?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

It is common practice to give high-dose prednisone to patients experiencing acute exacerbation of IPF, a relatively common (10-15% annual risk) and deadly event, but there are no good data to support its use. There is a significant risk of morbidity from this therapy. A well-designed multicenter trial could answer this question definitively.

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Goal 2: Reduce Human Disease

Interstitial Lung Disease

Do the non-pharmacological interventions of pulmonary rehabilitation and supplemental oxygen for exertional hypoxemia improve quality of life and functional status in patients with chronic fibrotic ILD?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

There is good evidence from small controlled trials that pulmonary rehabilitation improves walk distance and shortness of breath in patients with chronic ILD. Both pulmonary rehabilitation and supplemental oxygen are commonly recommended to these patients at great cost. A randomized clinical trial using factorial design could address the impact of these two therapies individually as well as together on clinically meaningful outcomes.

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Goal 2: Reduce Human Disease

Childhood Interstitial Lung Disease

What is the natural history of the best characterized ChILD disorders (surfactantrelated sequence variants, neuroendocrine cell hyperplasia of infancy (NEHI),pulmonary interstitial glycogenosis (PIG),idiopathic pulmonary hemosiderosis)?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

We know little about the natural history of many of the child entities, and their relative rarity makes it difficult for any one center to answer the major questions they pose. The children has begun a patient registry that will begin to address the issue of natural history and disease tracking.

 

a. To improve the power of such a registry, we suggest that support be provided to find novel methods to link this data base to available electronic medical records of participating centers in order to assess physiologic and other clinical associations with specific diseases.

 

b. Support for a biomarker repository holding serum, frozen and fixed lung tissue, patient DNA, RNA, and proteomic and metabolomic materials, and bronchoalveolar lavage effluent and cell pellets, will allow for genome wide analysis as well as proteomic and metabolomic analysis.

Feasibility and challenges of addressing this CQ or CC :

This question is best addressed in the context of a multicenter data registry, ideally linked to a clinical sample.

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Goal 2: Reduce Human Disease

Childhood Interstitial Lung Disease

What is the relationship of ChILD disorders to adult diffuse lung disease?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Feasibility and challenges of addressing this CQ or CC :

This would need to be addressed in the context of databases such as those for familial idiopathic pulmonary fibrosis (F-IPF) or IPF clinical trials, as well as perhaps databases for COPD and pulmonary hypertension. What is the prevalence and spectrum of childhood respiratory disease in family members within these cohorts? What is the prevalence of adult lung disease in family members in ChILD registries? In disorders such as surfactant-related sequence variants, which can cause disease across the lifespan, what are likely “2nd hits”, genomic or environmental, that may lead to clinical disease at particular ages/developmental stages?

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Goal 2: Reduce Human Disease

Childhood Interstitial Lung Disease

What is the relationship of ChILD disorders to more common childhood respiratory diseases?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

For example, what is the role of surfactant-related sequence variants in chronic lung disease of prematurity? Cystic fibrosis? Severe bronchiolitis? Refractory asthma?

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Goal 2: Reduce Human Disease

Childhood Interstitial Lung Disease

What is the relationship of ChILD disorders to other clinical populations that manifest ILD?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

ILD is a prominent feature of systemic inflammatory diseases, such as lupus. ILD is also among the most common long-term complications of therapy for childhood cancer. What is the relationship of surfactant-related sequence variants to expression of clinical ILD in these cohorts?

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Goal 2: Reduce Human Disease

Pulmonary Vascular Diseases

Does "goal-targeted" therapy (with adjustments/additional therapy, if certain "goals" are not achieved) improve quality of life, functional status, and survival in patients with pulmonary arterial hypertension? Trials of therapies for hepatopulmonary syndrome.

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Feasibility and challenges of addressing this CQ or CC :

This is a view of problems in the field.

Pulmonary Hypertension Clinical Research: Current Problems and Possibilities

Current studies limited to the short term, with soft outcomes.

No mechanistic studies embedded in trials.

Control of phenotype is weak.

Small n: lumping of cohorts.

No factorial of advanced design.

No biological samples obtained for study.

Failure to study basic management issues.

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Goal 2: Reduce Human Disease

Pulmonary Vascular Diseases

Does pulmonary rehabilitation or regular exercise improve outcomes in patients with PVD?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

This is a view of problems in the field.

Pulmonary Hypertension Clinical Research: Current Problems and Possibilities

Current studies limited to the short term, with soft outcomes.

No mechanistic studies embedded in trials.

Control of phenotype is weak.

Small n: lumping of cohorts.

No factorial of advanced design.

No biological samples obtained for study.

Failure to study basic management issues.

Name of idea submitter and other team members who worked on this idea : ATS Member

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Goal 2: Reduce Human Disease

Interaction with Office of Rare Diseases

NHLBI should engage more interactively with the Office of Rare Diseases (ORD).

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

There is a synergy that comes with collaboration with rare disease clinical science from other institutes. Some of this synergy is scientific, much of it falls into the support engendered to the patient support groups that are partners in filling the funding gap that many NHLBI initiatives have.

Feasibility and challenges of addressing this CQ or CC :

To go it alone in rare disease dissociates the lung disease clinicians from the huge movements in registry science that will impact the field for years to come.

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Goal 2: Reduce Human Disease

Rare Disease Biorepository

NHLBI should establish a rare disease biorepository that can be used by PhD and MD scientists, and propose new therapies based on the insights gained.

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

If you think about improving rare disease treatment, any clinical trial is better than no clinical trial. Although I make this point in jest, the important aspect is that the control group is actually as important as the treatment group in establishing the natural history of the disease, establishing a biorepository that can be used by PhD and MD scientists, and proposing new therapies based on the insights gained. I would use as an example the current GRADS program in sarcoidosis and Alpha-1 antitrypsin deficiency. My prediction is that we will find rather minor microbiome elements of disease pathogenesis (it is worth looking). However, the integrated genomics aspects of the protocols will be useful for a decade to stimulate discovery.

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Goal 2: Reduce Human Disease

Pulmonary Complications of Sickle Cell Disease

Do SCD patients with hemodynamics consistent with pulmonary arterial hypertension (PAH) respond to medications designed to treat PAH?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

What is known about this topic:

1) Case series have demonstrated potential therapeutic benefits for endothelin receptor antagonists, phosphodiesterase 5 inhibitors and prostacyclins in PH of SCD patients

2) Three attempted randomized placebo controlled trials of these agents in SCD patients have not gone to completion and, as a result, were under-powered to demonstrate efficacy.

3) Sildenafil produced an increase in hospitalization for pain crises in this population.

4) Anecdotally, select SCD patients with PAH have hemodynamic and clinical benefits from PAH medications.

5) Approximately ½ of PH in SCD patients have some degree of pulmonary venous hypertension and these medications may not be helpful here.

Feasibility and challenges of addressing this CQ or CC :

Areas of controversy:

1) Only one of the three randomized controlled trials required a PAH diagnosis prior to randomization, so the actual question hasn’t been properly addressed.

2) SCD patients with PAH are different than idiopathic PAH patients in terms of their underlying disease, so possibly the treatment response is different.

3) What are the right clinical trial endpoints for this population?

4) What is the role of SCD specific therapy (hydroxyurea, transfusions) in treating PAH of SCD?

5) How can investigators design a clinical trial which allows for enough patient accrual to achieve its endpoints?

6) What novel therapies can be developed to treat this population?

7) What unrecognized medication toxicities are SCD patients at increased risk for?

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