FROM: NEJEM
BACKGROUND
Although
several therapeutic agents have been evaluated for the treatment of coronavirus
disease 2019 (Covid-19), none have yet been shown to be efficacious.
METHODS
We
conducted a double-blind, randomized, placebo-controlled trial of intravenous
remdesivir in adults hospitalized with Covid-19 with evidence of lower
respiratory tract involvement. Patients were randomly assigned to receive
either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for
up to 9 additional days) or placebo for up to 10 days. The primary outcome was
the time to recovery, defined by either discharge from the hospital or
hospitalization for infection-control purposes only.
RESULTS
A total
of 1063 patients underwent randomization. The data and safety monitoring board recommended
early unblinding of the results on the basis of findings from an analysis that
showed shortened time to recovery in the remdesivir group. Preliminary results
from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with
data available after randomization indicated that those who received remdesivir
had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12),
as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate
ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier
estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with
placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse
events were reported for 114 of the 541 patients in the remdesivir group who
underwent randomization (21.1%) and 141 of the 522 patients in the placebo
group who underwent randomization (27.0%).
CONCLUSIONS
Remdesivir
was superior to placebo in shortening the time to recovery in adults
hospitalized with Covid-19 and evidence of lower respiratory tract infection.
(Funded by the National Institute of Allergy and Infectious Diseases and
others; ACCT-1 ClinicalTrials.gov number, NCT04280705. opens in new tab.)
A novel
coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was
first identified in December 2019 as the cause of a respiratory illness
designated coronavirus disease 2019, or Covid-19.1 Several therapeutic agents have been evaluated
for the treatment of Covid-19, but none have yet been shown to be efficacious.2,3 Remdesivir (GS-5734), an inhibitor of the
viral RNA-dependent, RNA polymerase with inhibitory activity against SARS-CoV
and the Middle East respiratory syndrome (MERS-CoV),4-7 was identified early as a promising
therapeutic candidate for Covid-19 because of its ability to inhibit SARS-CoV-2
in vitro.8 In addition, in nonhuman primate studies,
remdesivir initiated 12 hours after inoculation with MERS-CoV9,10 reduced lung virus levels and lung damage.
To
evaluate the clinical efficacy and safety of putative investigational
therapeutic agents among hospitalized adults with laboratory-confirmed
Covid-19, we designed an adaptive platform to rapidly conduct a series of phase
3, randomized, double-blind, placebo-controlled trials. Here, we describe the
preliminary results of the first stage of the Adaptive Covid-19 Treatment Trial
(ACTT-1), in which we evaluated treatment with remdesivir as compared with
placebo.
DESIGN
Enrollment
for ACTT-1 began on February 21, 2020, and ended on April 19, 2020. There were
60 trial sites and 13 subsites in the United States (45 sites), Denmark (8),
the United Kingdom (5), Greece (4), Germany (3), Korea (2), Mexico (2), Spain
(2), Japan (1), and Singapore (1). Eligible patients were randomly assigned in
a 1:1 ratio to receive either remdesivir or placebo. Randomization was
stratified by study site and disease severity at enrollment (see the Supplementary Appendix, available with the full text of this
article at NEJM.org, for details about stratification criteria). Remdesivir was
administered intravenously as a 200-mg loading dose on day 1, followed by a
100-mg maintenance dose administered daily on days 2 through 10 or until
hospital discharge or death. A matching placebo was administered according to
the same schedule and in the same volume as the active drug. A normal saline
placebo was used at the European sites and at some non-European sites owing to
a shortage of matching placebo; the infusions were masked with an opaque bag
and tubing covers to maintain blinding. All patients received supportive care
according to the standard of care for the trial site hospital. If a hospital
had a written policy or guideline for use of other treatments for Covid-19,
patients could receive those treatments. In the absence of a written policy or
guideline, other experimental treatment or off-label use of marketed
medications intended as specific treatment for Covid-19 were prohibited from
day 1 through day 29 (though such medications could have been used before
enrollment in this trial).
The trial
protocol was approved by the institutional review board at each site (or by a
centralized institutional review board as applicable) and was overseen by an
independent data and safety monitoring board. Informed consent was obtained
from each patient or from the patient’s legally authorized representative if
the patient was unable to provide consent. Full details of the trial design,
conduct, oversight, and analyses can be found in the protocol and statistical analysis plan (available at
NEJM.org).
PROCEDURES
Patients
were assessed daily during their hospitalization, from day 1 through day 29.
The patient’s clinical status on an eight-category ordinal scale (defined
below) and the National Early Warning Score was recorded each day.11,12 All serious adverse events and grade 3 or 4
adverse events that represented an increase in severity from day 1 and any
grade 2 or higher suspected drug-related hypersensitivity reactions were
recorded. (See the full description of trial procedures in the Supplementary Appendix.)
STATISTICAL ANALYSIS
The
primary analysis was a stratified log-rank test of the time to recovery with
remdesivir as compared with placebo, with stratification by disease severity.
(See the Supplementary Appendix for more information about the
planned statistical analysis.)
The
primary outcome measure was the time to recovery, defined as the first day,
during the 28 days after enrollment, on which a patient satisfied categories 1,
2, or 3 on the eight-category ordinal scale. The categories are as follows: 1,
not hospitalized, no limitations of activities; 2, not hospitalized, limitation
of activities, home oxygen requirement, or both; 3, hospitalized, not requiring
supplemental oxygen and no longer requiring ongoing medical care (used if
hospitalization was extended for infection-control reasons); 4, hospitalized,
not requiring supplemental oxygen but requiring ongoing medical care
(Covid-19–related or other medical conditions); 5, hospitalized, requiring any
supplemental oxygen; 6, hospitalized, requiring noninvasive ventilation or use
of high-flow oxygen devices; 7, hospitalized, receiving invasive mechanical
ventilation or extracorporeal membrane oxygenation (ECMO); and 8, death. Other outcomes
included mortality at 14 and 28 days after enrollment and grade 3 and 4 adverse
events and serious adverse events that occurred during the trial. Prespecified
subgroups in these analyses were defined according to sex, disease severity (as
defined for stratification and by ordinal scale at enrollment), age (18 to 39
years, 40 to 64 years, or 65 years of age or older), and duration of symptoms
before randomization (≤10 days or >10 days). (See the protocol for more information about the trial methods.)
The
primary outcome was initially defined as the difference in clinical status,
defined by the eight-category ordinal scale, among patients treated with
remdesivir as compared with placebo at day 15. This initial primary outcome
became the key secondary outcome after the change in primary outcome. The
change was proposed on March 22, 2020, by trial statisticians who were unaware
of treatment assignments and had no knowledge of outcome data. When this change
was proposed, 72 patients had been enrolled and no interim data were available.
The amendment was finalized on April 2, 2020, without any knowledge of outcome
data from the trial and before any interim data were available. This change in
primary outcome was made in response to evolving information, external to the
trial, indicating that Covid-19 may have a more protracted course than
previously appreciated.
On April
27, 2020, the data and safety monitoring board reviewed results. Although this
review was originally planned as an interim analysis, because of the rapid pace
of enrollment, the review occurred after completion of enrollment while
follow-up was still ongoing. At the time of the data and safety monitoring
board report, which was based on data cutoff date of April 22, 2020, a total of
482 recoveries (exceeding the estimated number of recoveries needed for the
trial) and 81 deaths had been entered in the database. At that time, the data
and safety monitoring board recommended that the preliminary primary analysis
report and mortality data from the closed safety report be provided to trial
team members from the National Institute of Allergy and Infectious Diseases
(NIAID). These results were subsequently made public; the treating physician
could request to be made aware of the treatment assignment of patients who had
not completed day 29 if clinically indicated (e.g., because of worsening
clinical status), and patients originally in the placebo group could be given
remdesivir. This report summarizes the preliminary results from this ongoing
trial.
PATIENTS
Of the
1107 patients who were assessed for eligibility, 1063 underwent randomization;
541 were assigned to the remdesivir group and 522 to the placebo group . Of those assigned to receive remdesivir, 531
patients (98.2%) received the treatment as assigned. Forty-nine patients had
remdesivir treatment discontinued before day 10 because of an adverse event or
a serious adverse event other than death (36 patients) or because the patient
withdrew consent (13). Of those assigned to receive placebo, 518 patients
(99.2%) received placebo as assigned. Fifty-three patients discontinued placebo
before day 10 because of an adverse event or a serious adverse event other than
death (36 patients), because the patient withdrew consent (15), or because the
patient was found to be ineligible for trial enrollment (2).
As of
April 28, 2020, a total of 391 patients in the remdesivir group and 340 in the
placebo group had completed the trial through day 29, recovered, or died. Eight
patients who received remdesivir and 9 who received placebo terminated their
participation in the trial before day 29. There were 132 patients in the
remdesivir group and 169 in the placebo group who had not recovered and had not
completed the day 29 follow-up visit. The analysis population included 1059
patients for whom we have at least some postbaseline data available (538 in the
remdesivir group and 521 in the placebo group). Four of the 1063 patients were
not included in the primary analysis because no postbaseline data were
available at the time of the database freeze.
The mean
age of patients was 58.9 years, and 64.3% were male . On the basis of the evolving epidemiology of
Covid-19 during the trial, 79.8% of patients were enrolled at sites in North
America, 15.3% in Europe, and 4.9% in Asia (Table S1). Overall, 53.2% of the
patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were
designated as other or not reported; 249 (23.4%) were Hispanic or Latino. Most
patients had either one (27.0%) or two or more (52.1%) of the prespecified
coexisting conditions at enrollment, most commonly hypertension (49.6%),
obesity (37.0%), and type 2 diabetes mellitus (29.7%).
The
median number of days between symptom onset and randomization was 9
(interquartile range, 6 to 12). Nine hundred forty-three (88.7%) patients had
severe disease at enrollment as defined in the Supplementary Appendix; 272 (25.6%) patients met category 7
criteria on the ordinal scale, 197 (18.5%) category 6, 421 (39.6%) category 5,
and 127 (11.9%) category 4. There were 46 (4.3%) patients who had missing
ordinal scale data at enrollment. No substantial imbalances in baseline
characteristics were observed between the remdesivir group and the placebo
group.
Patients
in the remdesivir group had a shorter time to recovery than patients in the
placebo group (median, 11 days, as compared with 15 days; rate ratio for
recovery, 1.32; 95% confidence interval [CI], 1.12 to 1.55; P<0.001; 1059
patients . Among patients with a baseline ordinal score of
5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84);
among patients with a baseline score of 4 (127 patients) and those with a
baseline score of 6 (197 patients), the rate ratio estimates for recovery were
1.38 (95% CI, 0.94 to 2.03) and 1.20 (95% CI, 0.79 to 1.81), respectively. For
those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal
scores of 7; 272 patients), the rate ratio for recovery was 0.95 (95% CI, 0.64
to 1.42). A test of interaction of treatment with baseline score on the ordinal
scale was not significant. An analysis adjusting for baseline ordinal score as
a stratification variable was conducted to evaluate the overall effect (of the
percentage of patients in each ordinal score category at baseline) on the
primary outcome. This adjusted analysis produced a similar treatment-effect
estimate (rate ratio for recovery, 1.31; 95% CI, 1.12 to 1.54; 1017 patients).
Table S2 in the Supplementary Appendix shows results according to the
baseline severity stratum of mild-to-moderate as compared with severe. Patients
who underwent randomization during the first 10 days after the onset of
symptoms had a rate ratio for recovery of 1.28 (95% CI, 1.05 to 1.57; 664
patients), whereas patients who underwent randomization more than 10 days after
the onset of symptoms had a rate ratio for recovery of 1.38 (95% CI, 1.05 to
1.81; 380 patients) .
KEY SECONDARY OUTCOME
The odds
of improvement in the ordinal scale score were higher in the remdesivir group,
as determined by a proportional odds model at the day 15 visit, than in the
placebo group (odds ratio for improvement, 1.50; 95% CI, 1.18 to 1.91; P=0.001;
844 patients) (Table 2 and Fig. S5). Mortality was numerically lower
in the remdesivir group than in the placebo group, but the difference was not
significant (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04; 1059
patients). The Kaplan–Meier estimates of mortality by 14 days were 7.1% and
11.9% in the remdesivir and placebo groups, respectively (Table 2). The Kaplan–Meier estimates of mortality by 28
days are not reported in this preliminary analysis, given the large number of
patients that had yet to complete day 29 visits. An analysis with adjustment
for baseline ordinal score as a stratification variable showed a hazard ratio
for death of 0.74 (95% CI, 0.50 to 1.10).
SAFETY OUTCOMES
Serious
adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141
patients (27.0%) in the placebo group (Table S3); 4 events (2 in each group)
were judged by site investigators to be related to remdesivir or placebo. There
were 28 serious respiratory failure adverse events in the remdesivir group
(5.2% of patients) and 42 in the placebo group (8.0% of patients). Acute
respiratory failure, hypotension, viral pneumonia, and acute kidney injury were
slightly more common among patients in the placebo group. No deaths were
considered to be related to treatment assignment, as judged by the site
investigators.
Grade 3
or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group
and in 172 in the placebo group (33.0%) (Table S4). The most common adverse
events in the remdesivir group were anemia or decreased hemoglobin (43 events
[7.9%], as compared with 47 [9.0%] in the placebo group); acute kidney injury,
decreased estimated glomerular filtration rate or creatinine clearance, or
increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]);
pyrexia (27 events [5.0%], as compared with 17 [3.3%]); hyperglycemia or
increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]);
and increased aminotransferase levels including alanine aminotransferase, aspartate
aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]).
Otherwise, the incidence of adverse events was not found to be significantly
different between the remdesivir group and the placebo group.
Preliminary
results of this trial suggest that a 10-day course of remdesivir was superior
to placebo in the treatment of hospitalized patients with Covid-19. This
benefit was seen in the number of days to recovery (median, 11 days, as
compared with 15; rate ratio for recovery, 1.32 [95% CI, 1.12 to 1.55]) and in
recovery according to the ordinal scale score at day 15 (odds ratio, 1.50; 95%
CI, 1.18 to 1.91). Even though the trial was ongoing, the data and safety
monitoring board made the recommendation to unblind the results to the trial
team members from the NIAID, who subsequently decided to make the results
public. Given the strength of the results about remdesivir, these findings were
deemed to be of immediate importance for the care of patients still
participating in the trial as well as for those outside the trial who might
benefit from treatment with remdesivir.
The
benefit was most apparent in patients with a baseline ordinal score of 5
(requiring oxygen), a finding most likely due to the larger sample size in this
category (since the interaction test of treatment by baseline score on the
ordinal scale was not significant). Confidence intervals for baseline ordinal
scores of 4 (not receiving oxygen), 6 (receiving high-flow oxygen), and 7
(receiving ECMO or mechanical ventilation) are wide. We note that the median
recovery time for patients in category 7 could not be estimated, which suggests
that the follow-up time may have been too short to evaluate this subgroup.
Additional analyses of outcomes such as the time to a one- or two-point
improvement on the ordinal scale score will be conducted after the full cohort
has completed 28 days of follow-up and may provide additional insight into the
treatment of this critical subgroup. Our findings highlight the need to
identify Covid-19 cases and start antiviral treatment before the pulmonary
disease progresses to require mechanical ventilation.
The
findings in our trial should be compared with those observed in a randomized
trial from China in which 237 patients were enrolled (158 assigned to
remdesivir and 79 to placebo).13The time to clinical improvement, defined as the
time to a two-point improvement in the score on the ordinal scale, was 21.0
days (95% CI, 13.0 to 28.0) in the remdesivir group and 23.0 days (95% CI, 15.0
to 28.0) in the control group, with a hazard ratio (for clinical improvement)
of 1.23 (95% CI, 0.87 to 1.75). The six-category ordinal scale used in that
trial yielded a common odds ratio for improvement in the ordinal score scale of
1.25 (95% CI, 0.76 to 2.04) at day 14. That trial failed to complete full
enrollment (owing to the end of the outbreak), had lower power than the present
trial (owing to the smaller sample size and a 2:1 randomization), and was
unable to demonstrate any statistically significant clinical benefits of
remdesivir.
The
primary outcome of the current trial was changed with protocol version 3 on
April 2, 2020, from a comparison of the eight-category ordinal scale scores on
day 15 to a comparison of time to recovery up to day 29. Little was known about
the natural clinical course of Covid-19 when the trial was designed in February
2020. Emerging data suggested that Covid-19 had a more protracted course than
was previously known, which aroused concern that a difference in outcome after
day 15 would have been missed by a single assessment at day 15. The amendment
was proposed on March 22, 2020, by trial statisticians who were unaware of
treatment assignment and had no knowledge of outcome data; when this change was
proposed 72 patients had been enrolled. Although changes in the primary outcome
are not common for diseases that are well understood, it is recognized that in
some trials, such as those involving poorly understood diseases, circumstances
may require a change in the way an outcome is assessed or may necessitate a
different outcome.14 The original primary outcome became the key
secondary end point. In the end, findings for both primary and key secondary
end points were significantly different between the remdesivir and placebo
groups.
Numerous
challenges were encountered during this trial. The trial was implemented during
a time of restricted travel, and hospitals restricted the entrance of nonessential
personnel. Training, site initiation visits, and monitoring visits often were
performed remotely. Research staff were often assigned other clinical duties,
and staff illnesses strained research resources. Many sites did not have
adequate supplies of personal protective equipment and trial-related supplies,
such as swabs. However, research teams were motivated to find creative
solutions to overcome these challenges.
The Food
and Drug Administration has made remdesivir available under an emergency-use authorization
for the treatment of adults and children with severe Covid-19 disease. Our
preliminary report is intended to help inform clinicians considering the use of
remdesivir. We are awaiting final visits, data entry, monitoring, and data lock
for the last of the 1063 patients enrolled, after which an update of the
results will be provided. To ensure the accuracy of the reported findings, we
evaluated the primary outcome, key secondary outcomes, and mortality results on
current data from May 18, 2020. The results were similar to those reported in
the Results section of this article. The full statistical analysis of the
entire trial population must occur, in order to fully understand the efficacy
of remdesivir in this trial.
These
preliminary findings support the use of remdesivir for patients who are
hospitalized with Covid-19 and require supplemental oxygen therapy. However,
given high mortality despite the use of remdesivir, it is clear that treatment
with an antiviral drug alone is not likely to be sufficient. Future strategies
should evaluate antiviral agents in combination with other therapeutic
approaches or combinations of antiviral agents to continue to improve patient
outcomes in Covid-19.
The trial
was sponsored and primarily funded by the National Institute of Allergy and
Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD.
This trial has been funded in part with federal funds from the NIAID and the
National Cancer Institute, NIH, under contract HHSN261200800001E 75N910D00024,
task order number 75N91019F00130/75N91020F00010, and by the Department of
Defense, Defense Health Program. This trial has been supported in part by the
NIAID of the NIH under award numbers UM1AI148684, UM1AI148576, UM1AI148573,
UM1AI148575, UM1AI148452, UM1AI148685, UM1AI148450, and UM1AI148689. The trial
has also been funded in part by the governments of Japan, Mexico, Denmark, and
Singapore. The trial site in South Korea received funding from the Seoul
National University Hospital. Support for the London International Coordinating
Centre was also provided by the United Kingdom Medical Research Council
(MRC_UU_12023/23).
Disclosure forms provided by the authors are available
with the full text of this article at NEJM.org.
The
content of this publication does not necessarily reflect the views or policies
of the Department of Health and Human Services, the Uniformed Services
University of the Health Sciences, the Henry M. Jackson Foundation for the
Advancement of Military Medicine, the Departments of the Army, Navy, or Air
Force, the Department of Defense, or the Department of Veterans Affairs, nor
does any mention of trade names, commercial products, or organizations imply
endorsement by the U.S. Government. Gilead Sciences provided remdesivir for use
in this trial but did not provide any financial support. Employees of Gilead
Sciences participated in discussions about protocol development and in weekly
protocol team calls. The NIAID ultimately made all decisions regarding trial
design and implementation.
This
article was published on May 22, 2020, at NEJM.org.
We thank
the members of the ACTT-1 Study Group (see the Supplementary Appendix) for their many contributions in
conducting the trial, the members of the Data and Safety Monitoring Board (Michael
G. Ison, M.D. [Chair], Northwestern University Feinberg School of Medicine;
Nina Singh, M.D., University of Pittsburgh; Bernd Salzberger, M.D., Ph.D.,
University of Regensburg; Wendy Leisenring, Sc.D., Fred Hutchinson Cancer
Research Center; and Peter Sasieni, Ph.D., King’s College London) for their
oversight, and the patients themselves for their altruism in participating in
this trial.
From the
National Institute of Allergy and Infectious Diseases, National Institutes of
Health (J.H.B., K.M.T., L.E.D., S.N., H.C.L.), and the Infectious Disease
Clinical Research Program, Uniformed Services University of the Health Sciences
(T.H.B.), Bethesda, the Clinical Monitoring Research Program Directorate,
Frederick National Laboratory for Cancer Research, Frederick (T. Bonnett), and
Emmes, Rockville (M.G., M.M.) — all in Maryland; Emory University, Atlanta
(A.K.M.); Montefiore Medical Center–Albert Einstein College of Medicine
(B.S.Z.) and NYU Langone Health and NYC Health + Hospitals– Bellevue (K.D.),
New York; University of Nebraska Medical Center, Omaha (A.C.K., M.G.K.);
Massachusetts General Hospital, Boston (E.H.), and University of Massachusetts
Medical School, Worcester (R.W.F.); University of Washington, Seattle (H.Y.C.),
and Evergreen Health Medical Center, Kirkland (D.L.C.) — both in Washington;
University of California, San Francisco, San Francisco (A.L.), Cedars Sinai
Medical Center, Los Angeles (V.T.), University of California, Irvine, Irvine
(L.H.), University of California, San Diego, La Jolla (D.A.S.), and Gilead
Sciences, Foster City (A.O.) — all in California; University of Minnesota
(S.K.) and University of Minnesota, School of Public Health and INSIGHT
(J.D.N.), Minneapolis; University of Texas Health San Antonio, University
Health System, and the South Texas Veterans Health Care System, San Antonio
(T.F.P.), and Baylor College of Medicine, Houston (R.L.A.); Hospital Germans
Trias i Pujol & irsiCaixa AIDS Research Institute, Badalona, Spain (R.P.);
University of Pennsylvania, Philadelphia (W.R.S.); Medical School, National and
Kapodistrian University of Athens, Athens (G.T.); National Center for
Infectious Diseases–Tan Tock Seng Hospital–Lee Kong Chian School of
Medicine–Yong Loo Lin School of Medicine, Singapore, Singapore (D.C.L.); the
National Center for Global Health and Medicine Hospital, Tokyo (N.O.); Seoul
National University Hospital, Seoul, South Korea (M.O.); Instituto Nacional de
Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (G.M.R.-P.); the
Department of Infectious Diseases, Amager Hvidovre Hospital–University of
Copenhagen, Hvidovre (T. Benfield), and Rigshospitalet, Department of
Infectious Diseases (CHIP) and INSIGHT, Copenhagen (J.L.) — both in Denmark;
University Hospital of Cologne, Cologne, Germany (G.F.); Vanderbilt University
Medical Center, Nashville (C.B.C.); and University College London, MRC Clinical
Trials Unit at UCL and INSIGHT, London (A.G.B., S.P.).
Address
reprint requests to Dr. Beigel at the National Institute of Allergy and Infectious
Diseases, National Institutes of Health, 5601 Fishers Ln., Rm. 7E60, MSC 9826,
Rockville, MD 20892-9826, or at jbeigel@niaid.nih.gov.
