A WORLDWIDE, PHASE III, RANDOMIZED, CONTROLLED, SAFETY AND EFFICACY STUDY OF A SIROLIMUS/CYCLOSPORINE REGIMEN FOR PREVENTION OF ACUTE REJECTION IN RECIPIENTS OF PRIMARY MISMATCHED RENAL ALLOGRAFTS
Bibliographic record
Abstract
BACKGROUND: Despite the various immunosuppressive regimens presently in use, acute rejection in the early postoperative period continues to occur in 20 to 40% of renal transplant patients. In a double-blind, multicentred study, we investigated the ability of two different doses of sirolimus (rapamycin, RAPAMUNE), a new class of immunosuppressant that blocks cell cycle progression, to prevent acute rejection in recipients of primary mismatched renal allografts when added to a regimen of cyclosporine (cyclosporin A, CsA) and corticosteroids. METHODS: Between October 1996 and September 1997, 576 recipients of primary mismatched cadaveric or living donor renal allografts were randomly assigned in a 2:2:1 ratio (before the transplant operation) to receive an initial loading dose of either 6 or 15 mg of orally administered sirolimus, followed by a daily dose of either 2 or 5 mg/day, or to receive a matched placebo. All groups received cyclosporine (microemulsion formula, CsA) and corticosteroids. The primary endpoint was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 6 months after transplantation. Safety data were monitored by an independent drug safety monitoring board. RESULTS: Based on an intention-to-treat analysis of 576 patients, there were no significant differences in patient demographic or baseline characteristics among treatment groups. The overall rate of the primary composite endpoint for the 6-month period after transplantation was 30.0% (68/227) in the 2 mg/day sirolimus group and 25.6% (56/219) in the 5 mg/day sirolimus group, significantly lower than the 47.7% (62/130) in the placebo group (P=0.002, P<0.001, respectively). During this period, the incidence of biopsy-confirmed acute rejection was 24.7% (56/227) in the 2 mg/day sirolimus group and 19.2% (42/219) in the 5 mg/day sirolimus group, compared with 41.5% (54/130) in the placebo group (P=0.003, P<0.001, respectively), representing a significant reduction in acute rejection of 40.5 and 53.7%, respectively. The need for antibody therapy to treat the first episode of biopsy-confirmed acute rejection was significantly reduced in the 5 mg/ day sirolimus group (3.2%) compared to the placebo group (8.5%; P=0.044). The results 1 year after transplantation were similar for the efficacy parameters studied. Adverse events and infections occurred in all groups. CONCLUSIONS: The addition of either 2 mg/day sirolimus or 5 mg/day sirolimus to CsA/corticosteroid therapy significantly reduces the incidence of acute rejection episodes in primary mismatched renal allograft recipients, without an increase in immunosuppressant-related side effects, including infections and malignancy, at 6 months and at 1 year after transplantation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.003 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".